Chemotherapy of Head and Chemotherapy of Head and Neck CancerNeck Cancer

April 2003April 2003

IntroductionIntroduction

500,000 new cases of squamous cell cancer 500,000 new cases of squamous cell cancer of the head and neck worldwide per year; of the head and neck worldwide per year; 40,00 new cases per year in the United States40,00 new cases per year in the United States

Despite continuing improvements in Despite continuing improvements in diagnosis, local management and diagnosis, local management and chemotherapy, there has been no significant chemotherapy, there has been no significant increase in survival rates over the past 30 increase in survival rates over the past 30 yearsyears

Chemotherapeutic AgentsChemotherapeutic Agents

Alkylating agentsAlkylating agents

AntimetabolitesAntimetabolites

Antitumor AntibioticsAntitumor Antibiotics

AlkaloidsAlkaloids

TaxanesTaxanes

Alkylating AgentsAlkylating Agents

Interact with DNA causing substitution Interact with DNA causing substitution reactions, cross-linking reactions or reactions, cross-linking reactions or strand breaksstrand breaks

CisplatinCisplatin

AntimetabolitesAntimetabolites

Cytotoxic effects via similarity in Cytotoxic effects via similarity in structure or function to naturally structure or function to naturally occurring metabolites involved in occurring metabolites involved in nucleic acid synthesis—either inhibit nucleic acid synthesis—either inhibit enzymes involved in nucleic acid enzymes involved in nucleic acid synthesis or produce incorrect codessynthesis or produce incorrect codes

MethotrexateMethotrexate

Antitumor AntibioticsAntitumor Antibiotics

Group of related antimicrobial compounds Group of related antimicrobial compounds produced by produced by StreptomycesStreptomyces species in species in cultureculture

Affect structure and function of nucleic Affect structure and function of nucleic acids by: intercalation between base pairs acids by: intercalation between base pairs (doxorubicin), DNA strand fragmentation (doxorubicin), DNA strand fragmentation (bleomycin), or cross-linking DNA (bleomycin), or cross-linking DNA (mitomycin)(mitomycin)

AlkaloidsAlkaloids

Bind free tubulin dimers thereby disrupting Bind free tubulin dimers thereby disrupting balance between microtubule balance between microtubule polymerization and depolymerization polymerization and depolymerization resulting in arrest of cells in metaphaseresulting in arrest of cells in metaphase

Examples: vincristine, vinblastineExamples: vincristine, vinblastine

TaxanesTaxanes

Disrupt equilibrium between free tubulin Disrupt equilibrium between free tubulin and microtubules causing stabilization of and microtubules causing stabilization of cytoplasmic microtubules and formation of cytoplasmic microtubules and formation of abnormal bundles of microtubules.abnormal bundles of microtubules.

Examples: paclitaxel and docetaxelExamples: paclitaxel and docetaxel

Neoadjuvant ChemotherapyNeoadjuvant Chemotherapy

Use of chemotherapy prior to definitive surgery Use of chemotherapy prior to definitive surgery or radiation therapyor radiation therapy

Intent is to improve both local and distant control Intent is to improve both local and distant control of disease in order to provide greater organ of disease in order to provide greater organ preservation and overall survivalpreservation and overall survival

Chemotherapy in neoadjuvant setting benefits Chemotherapy in neoadjuvant setting benefits from drug delivery to a tumor with vasculature from drug delivery to a tumor with vasculature not damaged by surgery or radiationnot damaged by surgery or radiation

Neoadjuvant ChemotherapyNeoadjuvant Chemotherapy

Standard induction chemotherapy is 5-Standard induction chemotherapy is 5-fluorouracil and cisplatinfluorouracil and cisplatinResponse rate between 68 and 93 Response rate between 68 and 93 percent; complete response as high as 54 percent; complete response as high as 54 percentpercentMust be followed by definitive surgery or Must be followed by definitive surgery or radiationradiationNo survival advantage even given No survival advantage even given decreased likelihood of distant metastasesdecreased likelihood of distant metastases

Neoadjuvant Therapy and Organ Neoadjuvant Therapy and Organ PreservationPreservation

Two large randomized, controlled trials Two large randomized, controlled trials have compared primary surgical have compared primary surgical management with a laryngeal preservation management with a laryngeal preservation approach of induction chemotherapy approach of induction chemotherapy followed by radiationfollowed by radiation

Survival comparable between groups; ½-Survival comparable between groups; ½-2/3 patients in the chemotherapy plus 2/3 patients in the chemotherapy plus radiation group retained larynxradiation group retained larynx

Concomitant ChemoradiotherapyConcomitant Chemoradiotherapy

Simultaneous use of chemotherapeutic Simultaneous use of chemotherapeutic agent and radiation therapyagent and radiation therapy

Intent is systemic control through Intent is systemic control through elimination of micro-metastases and elimination of micro-metastases and improved local control based on the improved local control based on the concepts of additivity and synergyconcepts of additivity and synergy

Adjuvant ChemotherapyAdjuvant Chemotherapy

Chemotherapeutic agents administered Chemotherapeutic agents administered after definitive treatment with radiation or after definitive treatment with radiation or chemotherapychemotherapy

The few studies that have been done The few studies that have been done failed to demonstrate any survival benefitfailed to demonstrate any survival benefit

Nasopharyngeal CarcinomaNasopharyngeal Carcinoma

Standard primary treatment is radiation Standard primary treatment is radiation therapytherapy

Several studies show increased survival Several studies show increased survival rates with concurrent cisplatin and rates with concurrent cisplatin and radiationradiation

Further survival benefits shown when this Further survival benefits shown when this regimen followed by cisplatin and 5-regimen followed by cisplatin and 5-fluorouracilfluorouracil

Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor

EGFR overexpression in many human EGFR overexpression in many human cancers including HNSCCcancers including HNSCC

EGFR blocking agents include anti-EGFR EGFR blocking agents include anti-EGFR antibodies and tyrosine kinase inhibitorsantibodies and tyrosine kinase inhibitors

IM-C225 is a monoclonal antibody IM-C225 is a monoclonal antibody targeting EGFR; combined with cisplatin targeting EGFR; combined with cisplatin has shown efficacy against HNSCChas shown efficacy against HNSCC

RASRAS

Farnesyl transferase inhibitors: class of Farnesyl transferase inhibitors: class of compounds that inhibit a critical step in the compounds that inhibit a critical step in the expression of the mutated ras genesexpression of the mutated ras genes

Farnesyl transferase inhibitors have been Farnesyl transferase inhibitors have been shown to decrease oral cavity tumor bulk; shown to decrease oral cavity tumor bulk; combined with paclitaxel it has shown combined with paclitaxel it has shown cytotoxic effects for head and neck cancer cytotoxic effects for head and neck cancer cell linescell lines

p53p53

Mutations of p53 occur in 45-70% of Mutations of p53 occur in 45-70% of HNSCCHNSCC

Ad-p53: adenovirus containing wild-type Ad-p53: adenovirus containing wild-type p53 genep53 gene

Preliminary studies of AD-p53 in patients Preliminary studies of AD-p53 in patients with advanced recurrent HNSCC showed with advanced recurrent HNSCC showed promising resultspromising results

ChemopreventionChemoprevention

One of the main reasons for treatment One of the main reasons for treatment failure in early stage HNSCC is failure in early stage HNSCC is development of a second primarydevelopment of a second primary

Chemoprevention: the process of field Chemoprevention: the process of field cancerization can be interrupted or cancerization can be interrupted or reversed through the use of natural or reversed through the use of natural or synthetic agentssynthetic agents

RetinoidsRetinoids

Retinoids have been shown to cause Retinoids have been shown to cause regression or stabilization of leukoplakiaregression or stabilization of leukoplakia

Recent use of 13-cis retinoic acid in Recent use of 13-cis retinoic acid in patients curatively treated for HNSCC patients curatively treated for HNSCC showed that second primary tumors showed that second primary tumors developed in only 4% of patients treated developed in only 4% of patients treated with 13-cis retinoic acid compared with with 13-cis retinoic acid compared with 24% of controls at 32 months24% of controls at 32 months

COX-2 inhibitorsCOX-2 inhibitors

Increased levels of COX-2 are found in Increased levels of COX-2 are found in oral leukoplakia and SCC as well as oral leukoplakia and SCC as well as normal appearing mucosa adjacent to normal appearing mucosa adjacent to HNSCCHNSCC

Sulindac, an NSAID and celecoxib, a Sulindac, an NSAID and celecoxib, a selective COX-2 inhibitor have been selective COX-2 inhibitor have been shown to reduce the number of colorectal shown to reduce the number of colorectal polyps in patients with FAPpolyps in patients with FAP

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