chemotherapy ppt

Chemotherapy and Why we Leave it to The Oncologists

Vanessa Rothholtz, M.D., M.Sc.Vanessa Rothholtz, M.D., M.Sc.

Department of Otolaryngology - Department of Otolaryngology - Head and Neck SurgeryHead and Neck Surgery

UCI Medical CenterUCI Medical Center

Introduction Describe the cell cycle and the phase that is Describe the cell cycle and the phase that is

affected by chemotherapeutic agents affected by chemotherapeutic agents Classification, Mechanism of Action and Side Classification, Mechanism of Action and Side

Effects of common agents used in the treatment of Effects of common agents used in the treatment of squamous cell carcinomasquamous cell carcinoma

Definition of the terms “induction” “concurrent” Definition of the terms “induction” “concurrent” “neoadjuvant” and “adjuvant” in relation to “neoadjuvant” and “adjuvant” in relation to chemotherapychemotherapy

Role of chemotherapy in the management of head Role of chemotherapy in the management of head and neck cancer as a single modality treatmentand neck cancer as a single modality treatment

Role of combination chemotherapy in the Role of combination chemotherapy in the management of head and neck cancer treatmentmanagement of head and neck cancer treatment

Introduction Organ preservation – VA Larynx Study, Duke Organ preservation – VA Larynx Study, Duke

Protocol Protocol Side effects of chemotherapeutic agents used in Side effects of chemotherapeutic agents used in

treatment of head and neck cancer treatment of head and neck cancer Measures that exist to reduce side effectsMeasures that exist to reduce side effects Concurrent chemotherapy combined with Concurrent chemotherapy combined with

radiation. Additional toxicity.radiation. Additional toxicity. Chemoprevention with RetinoidsChemoprevention with Retinoids Intra-arterial chemotherapy for head and neck Intra-arterial chemotherapy for head and neck

cancercancer New chemotherapeutic agentsNew chemotherapeutic agents

G1Phase: Growth. G1Phase: Growth. S Phase: DNA-synthesis S Phase: DNA-synthesis

and replication. and replication. G2 Phase: the cell checks G2 Phase: the cell checks

that DNA-replication is that DNA-replication is completed and prepares completed and prepares for cell division. for cell division.

M Phase: The M Phase: The chromosomes are chromosomes are separated (mitosis, M) separated (mitosis, M) and the cell divides into and the cell divides into two daughter cells. two daughter cells.

Chemotherapeutic Agents and the Cell Cycle

From: Milas L, Mason KA, Liao Z, Ang KK Chemoradiotherapy: emerging treatment improvement strategies. Head Neck. 2003 Feb;25(2):152-67

Classification of Chemotherapeutic Agents

Alkylating Agents: Cisplatin, Carboplatin, MelphalanAlkylating Agents: Cisplatin, Carboplatin, Melphalan

Antimetabolites: Methotrexate, 5-FUAntimetabolites: Methotrexate, 5-FU

Antitumor Antibiotics: Doxorubicin, Adriamycin, Bleomycin, Mitomycin-C, Antitumor Antibiotics: Doxorubicin, Adriamycin, Bleomycin, Mitomycin-C, IfosfamideIfosfamide

Alkaloids: Vincristine,Vinblastine, VinorelbineAlkaloids: Vincristine,Vinblastine, Vinorelbine

Taxanes: Paclitaxel and docetaxel.Taxanes: Paclitaxel and docetaxel.

Nucleoside analogues: Gemcitabine, Fludarabine, Cytosine arabinosideNucleoside analogues: Gemcitabine, Fludarabine, Cytosine arabinoside Nitrosoureas: BCNU, CCNUNitrosoureas: BCNU, CCNU Topoisomerase inhibitors: Topotecan, EtoposideTopoisomerase inhibitors: Topotecan, Etoposide HydroxyureaHydroxyurea


Alkylating AgentsAlkylating Agents: : Substitution reactions, cross-linking reactions Substitution reactions, cross-linking reactions

or strand-breaking reactions of DNA. or strand-breaking reactions of DNA. Alter the information coded in the DNA Alter the information coded in the DNA

molecule resulting in inhibition of or molecule resulting in inhibition of or inaccurate DNA replication with resultant inaccurate DNA replication with resultant mutation or cell death. mutation or cell death.

Classification of Chemotherapeutic AgentsAlkylating Agents Mechanism of Cisplatin / Carboplatin Inorganic metal coordination complexInorganic metal coordination complex Bifunctional alkylating agent binding to DNA to Bifunctional alkylating agent binding to DNA to

cause interstrand and intrastrand cross-linking.cause interstrand and intrastrand cross-linking. Binds to nuclear and cytoplasmic proteins.Binds to nuclear and cytoplasmic proteins. Resistance is believed to develop through Resistance is believed to develop through

increased metabolic inactivationincreased metabolic inactivation

Classification of Chemotherapeutic AgentsAlkylating Agents Adverse Effects of Cisplatin / Carboplatin Renal dysfunctionRenal dysfunction Hematologic toxicity - neutropenia, thrombocytopeniaHematologic toxicity - neutropenia, thrombocytopenia Bone Marrow Suppression - acute hemolytic anemia.Bone Marrow Suppression - acute hemolytic anemia. HypomagnesemiaHypomagnesemia OtotoxicityOtotoxicity Peripheral Neuropathy -neurotoxicityPeripheral Neuropathy -neurotoxicity


AntimetabolitesAntimetabolites. . Exerts cytotoxic effects by virtue of structural or Exerts cytotoxic effects by virtue of structural or

functional similarity to naturally occurring functional similarity to naturally occurring metabolites involved in nucleic acid synthesis.metabolites involved in nucleic acid synthesis.

Inhibits critical enzymes involved in nucleic acid Inhibits critical enzymes involved in nucleic acid synthesis.synthesis.

Incorporates into the nucleic acid and produces Incorporates into the nucleic acid and produces incorrect codes.incorrect codes.

Resulting in inhibition of DNA synthesis and Resulting in inhibition of DNA synthesis and ultimate cell death. ultimate cell death.

Classification of Chemotherapeutic AgentsAntimetabolites Mechanism of Methotrexate

Folic acid analog that is S-phase specificFolic acid analog that is S-phase specific Binds to the enzyme dihydrofolate reductase, that blocks Binds to the enzyme dihydrofolate reductase, that blocks

the reduction of dihydrofolate to tetrahydrofolic acid the reduction of dihydrofolate to tetrahydrofolic acid which is necessary for the synthesis of thymidylic acid which is necessary for the synthesis of thymidylic acid and purine. and purine.

Interrupts the synthesis of DNA, RNA, and protein.Interrupts the synthesis of DNA, RNA, and protein. Mechanisms for resistance to methotrexate include:Mechanisms for resistance to methotrexate include:

Selection of cells with decreased transport of Selection of cells with decreased transport of methotrexate into cellsmethotrexate into cells

Increased dihydrofolate reductase activity.Increased dihydrofolate reductase activity.

Classification of Chemotherapeutic AgentsAntimetabolites Adverse Effects of Methotrexate

Mild stomatitisMild stomatitis MyelosuppressionMyelosuppression Confluent mucositisConfluent mucositis PancytopeniaPancytopenia Liver function abnormalitiesLiver function abnormalities Exfoliative maculopapular rash Exfoliative maculopapular rash Renal dysfunctionRenal dysfunction

Classification of Chemotherapeutic AgentsAntimetabolites Mechanism of 5-Fluorouracil

Fluorinated pyrimidine similar to uracilFluorinated pyrimidine similar to uracil 5-FU competes for the enzyme thymidylate 5-FU competes for the enzyme thymidylate

synthetase by displacing uracil.synthetase by displacing uracil. Inhibits the formation of thymidine, an essential Inhibits the formation of thymidine, an essential

factor in DNA synthesisfactor in DNA synthesis

Classification of Chemotherapeutic AgentsAntimetabolites Adverse Effects of 5-Fluorouracil

MyelosuppressionMyelosuppression NeutropeniaNeutropenia Thrombocytopenia occurring at 1 or 2 weeks.Thrombocytopenia occurring at 1 or 2 weeks. Nausea, vomiting, and diarrheaNausea, vomiting, and diarrhea StomatitisStomatitis AlopeciaAlopecia HyperpigmentationHyperpigmentation Maculopapular rashMaculopapular rash


Anti-tumor AntibioticsAnti-tumor Antibiotics. . Group of related anti-microbial compounds Group of related anti-microbial compounds

produced by Streptomyces species in culture.produced by Streptomyces species in culture. Affect the structure and function of nucleic acids by:Affect the structure and function of nucleic acids by:

Intercalation between DNA base pairs Intercalation between DNA base pairs (doxorubicin - adriamycin)(doxorubicin - adriamycin)

DNA strand fragmentation (bleomycin)DNA strand fragmentation (bleomycin)Cross-linking of DNA (mitomycin, ifosfamide)Cross-linking of DNA (mitomycin, ifosfamide)


AlkaloidsAlkaloids.. Bind to free tubulin dimersBind to free tubulin dimers Disrupt the balance between microtubule Disrupt the balance between microtubule

polymerization and depolymerization, polymerization and depolymerization, resulting in the net dissolution of resulting in the net dissolution of microtubules, destruction of the mitotic microtubules, destruction of the mitotic spindle, and arrest of cells in metaphase. spindle, and arrest of cells in metaphase.


TaxanesTaxanes.. Disrupt equilibrium between free tubulin and Disrupt equilibrium between free tubulin and

microtubules causing stabilization of ordinary microtubules causing stabilization of ordinary cytoplasmic microtubules and the formation cytoplasmic microtubules and the formation of abnormal bundles of microtubules.of abnormal bundles of microtubules.

Single Agent ChemotherapyCriteria for Response

Complete response

Complete disappearance of all evidence of tumor for at least 4 weeks.

Partial response Disease regression by at least 50% of the sum of the product of the perpendicular diameters of all measurable tumor for at least 4 weeks. No simultaneous increase in the size of any lesion or appearance of new lesions may occur.

Minor response Regression by less than 50% of the sum of the products of the perpendicular diameters of all measurable lesions.

Stable disease No appreciable change in dimensions of all evaluable lesions.

Progressive disease

Increase in the size of any detectable lesions by at least 25% or the appearance of new lesions.

Single Agent Chemotherapy

Agent Dosing Schedule Response Rate (%)

Methotrexate 40–50 mg/m2 weekly 30

Cisplatin 80–120 mg/m2 every 3–4 weeks 33

Carboplatin 400 mg/m2 every 4 weeks 24

Paclitaxel 135–200 mg/m2 every 3–4 weeks 38

Docetaxel 75 mg/m2 every 3 weeks 38

Ifosfamide 1.5–2.5 g/m2 every 4 weeks 26

Bleomycin 15 mg/m2 twice weekly 18

5-Fluorouracil 500 mg/m2 weekly 15

Induction Chemotherapy Chemotherapy before surgery or radiotherapyChemotherapy before surgery or radiotherapy Promotes regression of tumorPromotes regression of tumor Enhances local-regional therapy via sensitizationEnhances local-regional therapy via sensitization Identifies patients who might be candidates for a Identifies patients who might be candidates for a

more conservative surgical approach more conservative surgical approach Treats micrometastatic disease in hopes of Treats micrometastatic disease in hopes of

reducing distant failure rates, which can be 40% or reducing distant failure rates, which can be 40% or greater with conventional local-regional greater with conventional local-regional surgical/radiation approachessurgical/radiation approaches

Improves the ability to identify responding tumors Improves the ability to identify responding tumors that might benefit from adjuvant chemotherapythat might benefit from adjuvant chemotherapy

Concurrent Chemotherapy

Used primarily in patients with unresectable disease Used primarily in patients with unresectable disease to improve local and regional controlto improve local and regional control

Interaction between cytotoxic drugs and radiation Interaction between cytotoxic drugs and radiation that results in additive or synergistic enhancement that results in additive or synergistic enhancement due to: due to: Inhibition of DNA repairInhibition of DNA repair Redistribution of cells in sensitive phases of the Redistribution of cells in sensitive phases of the

cell cyclecell cycle Promotion of oxygenation of anoxic tissuesPromotion of oxygenation of anoxic tissues

Neoadjuvant Chemotherapy

The application of chemotherapy prior to any other The application of chemotherapy prior to any other anticancer therapyanticancer therapy

Provides earlier exposure of potential Provides earlier exposure of potential micrometastases to chemotherapy than is achieved micrometastases to chemotherapy than is achieved with the standard adjuvant approachwith the standard adjuvant approach

Objective response to chemotherapy in the primary Objective response to chemotherapy in the primary lesion provides important in vivo evidence that the lesion provides important in vivo evidence that the therapy being used has anti-tumor activity and therapy being used has anti-tumor activity and suggests that the tumor at remote subclinical sites suggests that the tumor at remote subclinical sites will be sensitive as wellwill be sensitive as well

Adjuvant Chemotherapy

Extension of chemotherapy treatment for Extension of chemotherapy treatment for patients who remain at high risk of patients who remain at high risk of recurrence after the primary tumor and all recurrence after the primary tumor and all evidence of cancer have been surgically evidence of cancer have been surgically removed or treated definitively with removed or treated definitively with radiation. radiation.

Combination Chemotherapy Cisplatin and continuous infusion Bleomycin - 71% Cisplatin and continuous infusion Bleomycin - 71%

overall response rate with complete responses noted overall response rate with complete responses noted in 21% of patients in 21% of patients (Wittes, et al.)(Wittes, et al.)

Neoadjuvant cisplatin with infusion 5-fluorouracil Neoadjuvant cisplatin with infusion 5-fluorouracil (5-FU) - 88% overall response rate with complete (5-FU) - 88% overall response rate with complete response rate of 54%response rate of 54% 120-hour > 96-hour infusion 5-fluorouracil120-hour > 96-hour infusion 5-fluorouracil Three to five cycles > two cyclesThree to five cycles > two cycles

Metanalysis by Browman and Cronin found a more Metanalysis by Browman and Cronin found a more conservative statistic with overall response rates of conservative statistic with overall response rates of cisplatin and 5-FU to be 32%, and the complete cisplatin and 5-FU to be 32%, and the complete response rate ranging from 5% to 15%response rate ranging from 5% to 15%

ChemoradiationMechanism of Interaction

Increase in initial radiation damageIncrease in initial radiation damage Inhibition of cellular repairInhibition of cellular repair Cell cycle effects Cell cycle effects

Elimination of radioresistant S-phase cellsElimination of radioresistant S-phase cells Arrest in radiosensitive G2 or MArrest in radiosensitive G2 or M

Counteracting radioresistance caused by hypoxic Counteracting radioresistance caused by hypoxic cellscells Elimination of hypoxic cellsElimination of hypoxic cells Increase in tumor oxygenation through cell lossIncrease in tumor oxygenation through cell loss

Overcoming accelerated repopulationOvercoming accelerated repopulation

Chemoradiation Trials

Numerous Trials with Numerous Trials with

conflicting / equivocal resultsconflicting / equivocal results

Organ Preservation

Hanna et al. - 2004Hanna et al. - 2004 Duke Chemoradiation Protocol - 1998Duke Chemoradiation Protocol - 1998 VA study - 1991VA study - 1991

EfficacyEfficacy Toxic EffectsToxic Effects LimitationsLimitations

Organ PreservationHanna - Demographics

Ninety-six (76%) men Ninety-six (76%) men Thirty-one (24%) womenThirty-one (24%) women Average age at diagnosis - 62 years (37-85 years)Average age at diagnosis - 62 years (37-85 years) Primary tumor sitePrimary tumor site

Oropharynx 58 patients (46%)Oropharynx 58 patients (46%) Larynx 36 patients (28%)Larynx 36 patients (28%) Hypopharynx 20 patients (16%)Hypopharynx 20 patients (16%) Oral cavity 10 patients (8%)Oral cavity 10 patients (8%) Other 3 patients (2%)Other 3 patients (2%)

Ninety-one (91%) stage III or IV diseaseNinety-one (91%) stage III or IV disease

Organ PreservationHanna - Treatment

Standard fractionation radiotherapy (total dose of Standard fractionation radiotherapy (total dose of 66-72 Gy) 66-72 Gy)

At least 2 cycles of cisplatin and fluorouracilAt least 2 cycles of cisplatin and fluorouracil

concurrently with radiotherapy. concurrently with radiotherapy. Of the 127 patients, 44 alsoOf the 127 patients, 44 also received an additionalreceived an additional 2 2

cycles of neoadjuvant chemotherapy before starting cycles of neoadjuvant chemotherapy before starting concurrentconcurrent chemoradiotherapychemoradiotherapy

Patients with less than a complete responsePatients with less than a complete response to to chemoradiotherapy underwent salvage surgerychemoradiotherapy underwent salvage surgery

Organ PreservationHanna - Outcomes

Complete response at the primary tumor site - 109 Complete response at the primary tumor site - 109 patients (86%)patients (86%)

Local disease control - 113 patients (89%)Local disease control - 113 patients (89%) Organ preservation - 102 patients (80%). Organ preservation - 102 patients (80%). Clinical N+ disease - 83/127 patientsClinical N+ disease - 83/127 patients

Complete clinical response - 57 patients (69%)Complete clinical response - 57 patients (69%)N1 - 93%N1 - 93%N2 - 62%N2 - 62%N3 - 47%N3 - 47%

Regional disease control - 76/83 (92%) Regional disease control - 76/83 (92%) Distant metastasis - 18 patients (14%)Distant metastasis - 18 patients (14%)

Organ PreservationHanna - Outcomes

Disease-specific survival 72%Disease-specific survival 72% Overall survival 57%Overall survival 57% Severe Side EffectsSevere Side Effects

Severe (grade 3 or 4) mucositis - 33% Severe (grade 3 or 4) mucositis - 33% Neutropenia - 25%Neutropenia - 25% Death - 2 patientsDeath - 2 patients

Organ PreservationDuke Protocol

Organ PreservationDuke Protocol - Demographics/Treatment

Stage III/IV and Base of Tongue T2N0 Stage III/IV and Base of Tongue T2N0 Chemotherapy (fluorouracil and cisplatin) Chemotherapy (fluorouracil and cisplatin)

was administered at weeks 1 and 6 followed was administered at weeks 1 and 6 followed by two additionalby two additional cycles of cisplatin and cycles of cisplatin and fluorouracil after thefluorouracil after the completion of all local completion of all local therapy, with the cisplatin again dividedtherapy, with the cisplatin again divided into into five daily boluses, and the dose increased in five daily boluses, and the dose increased in cycle 3 and in cyclecycle 3 and in cycle 4.4.

Organ PreservationDuke Protocol - Overall Survival

Organ PreservationDuke Protocol - Disease Free Survival

Organ PreservationDuke Protocol - Randomization?

Imbalances in the twoImbalances in the two treatment groups:treatment groups: More patients with advanced nodalMore patients with advanced nodal disease (N2 or disease (N2 or

N3) in hyperfractionation group than in theN3) in hyperfractionation group than in the

combined-treatment group (63% vs. 45%)combined-treatment group (63% vs. 45%) More patients with hypopharynx as a primary site More patients with hypopharynx as a primary site

(which(which is associated with a less favorable result) in is associated with a less favorable result) in the combined-treatmentthe combined-treatment group and more patients group and more patients with oropharynx (tonsil and basewith oropharynx (tonsil and base of tongue) as a of tongue) as a primary site (which is associated with a moreprimary site (which is associated with a more

favorable result) in the hyperfractionation groupfavorable result) in the hyperfractionation group

The VA Study

Patients: Stage III or IV laryngeal SCCAPatients: Stage III or IV laryngeal SCCA Two groups: Two groups:

Induction chemotherapy (Cisplatin and 5-Induction chemotherapy (Cisplatin and 5-FU three cycles) followed by definitive FU three cycles) followed by definitive radiation therapy (6600 to 7600 cGy)radiation therapy (6600 to 7600 cGy)

Conventional laryngectomy and post-Conventional laryngectomy and post-operative radiationoperative radiation

The VA StudyOutcomesCauses of Death According to Treatment Assignment

Cause Surgery (N = 166)

Chemotherapy (N=166)

Cancer 38 (23%) 42 (25%)

Complication of therapy

4 (2) 4 (2)

Other 14(8) 6(4)

Unknown 2(1) 6(4)

All 58(35) 65 (39)

The VA StudyOutcomesPatterns of Tumor Recurrence According to Treatment Group

Site of Recurrence Surgery Chemotherapy

Primary 4 (2) 20(12)

Regional 9(5) 14(8)

Distant 29(17) 18(11)

All 42(25) 52(31)

The VA StudyOutcomesSalvage Laryngectomy

For persistent disease before radiation therapy or For persistent disease before radiation therapy or within three months afterward - 29% (48/166)within three months afterward - 29% (48/166)

For later recurrent disease - 7% (11/166)For later recurrent disease - 7% (11/166) Glottic cancers > Supraglottic cancers Glottic cancers > Supraglottic cancers Fixed vocal cords > Mobile cordsFixed vocal cords > Mobile cords Gross invasion of cartilage > No invasion Gross invasion of cartilage > No invasion Stage IV cancers > Stage III (44% vs. 29%)Stage IV cancers > Stage III (44% vs. 29%) T4 > smaller primary tumors (56%vs. 29%) T4 > smaller primary tumors (56%vs. 29%)

Nasopharyngeal Carcinoma

147 randomized patients - Stage III or IV147 randomized patients - Stage III or IV Radiotherapy alone vs. Cisplatin (100 mg/mRadiotherapy alone vs. Cisplatin (100 mg/m22 days days

1, 22, and 43) during radiotherapy followed by 1, 22, and 43) during radiotherapy followed by adjuvant chemotherapy with cisplatin and 5-FU adjuvant chemotherapy with cisplatin and 5-FU (three cycles)(three cycles)

3-year survival time (78% vs 47%)3-year survival time (78% vs 47%) Progression-free survival time (69% vs 24%)Progression-free survival time (69% vs 24%)

Side Effects

Marked increase in acute toxicityMarked increase in acute toxicity Mucositis Mucositis Dermatitis Dermatitis Increased risk of infectionIncreased risk of infection**

Poor nutritional intakePoor nutritional intake Interruption of radiotherapyInterruption of radiotherapy Chemotherapy dose reductionsChemotherapy dose reductions

Side EffectsAgent Toxicity

Cyclophosphamide Neutropenia, nausea, cystitis

Ifosfamide Myelosuppression, cystitis, confusion, alopecia

Methotrexate Mucositis, myelosuppression

5-Fluorouracil Mucositis, myelosuppression, diarrhea

Bleomycin Pulmonary fibrosis, rash, mucositis

Adriamycin Cardiotoxicity, mucositis, myelosuppression,alopecia

Vincristine Neurotoxicity, myelosuppression, alopecia

Vinblastine Neurotoxicity, myelosuppression, alopecia

Cisplatin Nephrotoxicity, vomiting, ototoxicity, neuropathy

Carboplatin Myelosuppression

Paclitaxel Myelosuppression, neuropathy

Docetaxel Edema, neutropenia, neuropathy

Side Effects Acute Mucositis

Side EffectsAcute Mucositis

Long-term dysphagiaLong-term dysphagia Thick,Thick, ropey, copious oropharyngealropey, copious oropharyngeal Secretions interfere with swallowing,Secretions interfere with swallowing, cause cause

gagging and regurgitation, and predispose gagging and regurgitation, and predispose to aspirationto aspiration

The limiting factorThe limiting factor

Side EffectsAcute Mucositis and Dysphagia

PatientsPatients with nasogastric feeding tubes may with nasogastric feeding tubes may have less long-term dysphagia, feeding tube have less long-term dysphagia, feeding tube duration,duration, and need for pharyngoesophageal and need for pharyngoesophageal dilationdilation

Nothing-by-mouthNothing-by-mouth (NPO) intervals as short (NPO) intervals as short as 2 weeks have been shown to predictas 2 weeks have been shown to predict poor poor swallowing outcomesswallowing outcomes

Side EffectsAcute Mucositis - Treatment

Polymyxin E, Tobramycine, and Amphotericin BPolymyxin E, Tobramycine, and Amphotericin B Granulocyte macrophage-colony-stimulating factor, Granulocyte macrophage-colony-stimulating factor,

Granulocyte colony-stimulating factor (GM-CSF/G-CSF)Granulocyte colony-stimulating factor (GM-CSF/G-CSF) Oral coolingOral cooling Amifostine - Ethyol - Organic thiophosphate. It has a Amifostine - Ethyol - Organic thiophosphate. It has a

higher alkaline phosphatase activity, higher pH and higher alkaline phosphatase activity, higher pH and vascular permeation of normal tissuesvascular permeation of normal tissues

Palmifermin - Recombinant human keratinocyte growth Palmifermin - Recombinant human keratinocyte growth factorfactor

Side EffectsAcute Mucositis - Amifostine

Patients:Patients: Radiation therapy twice daily - 1.6-gray (Gy) fractions up Radiation therapy twice daily - 1.6-gray (Gy) fractions up

to a total of 70.4 Gy over 6.5 weeksto a total of 70.4 Gy over 6.5 weeks Paclitaxel 60 mg/mPaclitaxel 60 mg/m22 once weekly starting on Day 1 once weekly starting on Day 1 Number of doses of paclitaxel increased from three to sixNumber of doses of paclitaxel increased from three to six Amifostine - 400 mg/mAmifostine - 400 mg/m22 IV on Days 1-5, 8, 29-33, and 36 IV on Days 1-5, 8, 29-33, and 36 Amifostine + Paclitaxel Amifostine + Paclitaxel

Additional dose of treatment (5 vs. 4) Additional dose of treatment (5 vs. 4)

Side EffectsAcute Mucositis - Palmifermin

106 patients - palifermin (60 µg/kg/day) 106 patients - palifermin (60 µg/kg/day) Incidence of grade 3 or 4 oral mucositis - 63 %Incidence of grade 3 or 4 oral mucositis - 63 % Duration - 3 days (0 to 22)Duration - 3 days (0 to 22) Less soreness of mouth, less use of morphine and TPNLess soreness of mouth, less use of morphine and TPN

106 patients - placebo106 patients - placebo Incidence of grade 3 or 4 oral mucositis - 98 %Incidence of grade 3 or 4 oral mucositis - 98 % Duration - 9 days (0 to 27)Duration - 9 days (0 to 27) Grade 4 oral mucositis - 62%Grade 4 oral mucositis - 62%

Adverse events - Rash, pruritus, erythema, mouth and Adverse events - Rash, pruritus, erythema, mouth and tongue disorders, and taste alterationtongue disorders, and taste alteration

Side EffectsNeuropathy and Vitamin E

Thirty-one patientsThirty-one patients

Six courses of cumulative cisplatin, paclitaxel, or bothSix courses of cumulative cisplatin, paclitaxel, or both

Group I (n = 16) - oral vitamin E at a daily dose of 600 Group I (n = 16) - oral vitamin E at a daily dose of 600 mg/day during chemotherapy and 3 months after its mg/day during chemotherapy and 3 months after its cessationcessation

Neurotoxicity - occurred in 4/16 (25%) patientsNeurotoxicity - occurred in 4/16 (25%) patients

Group II (n = 15) - no supplementationGroup II (n = 15) - no supplementation

Neurotoxicity - occurred in 11/15 (73.3%) patientsNeurotoxicity - occurred in 11/15 (73.3%) patients

Chemoprevention Bioadjuvant Therapy

Second primary malignancies develop at a Second primary malignancies develop at a rate of 3% to 4% per year in patients who rate of 3% to 4% per year in patients who

are curatively treated for an early stage head are curatively treated for an early stage head and neck squamous cell cancerand neck squamous cell cancer

Chemoprevention Retinoids

Retinoids have been shown to modify Retinoids have been shown to modify genomic expression at the level of genomic expression at the level of messenger RNA synthesis and to regulate messenger RNA synthesis and to regulate transcription of specific genestranscription of specific genes

Prevent malignant transformation of Prevent malignant transformation of dysplastic leukoplakia lesionsdysplastic leukoplakia lesions

Prevent second primary cancersPrevent second primary cancers

Chemoprevention Retinoids

Retinoid use in Oral LeukoplakiaRetinoid use in Oral Leukoplakia Complete response - 10-27% of patientsComplete response - 10-27% of patients Partial response - 54-90% of patientsPartial response - 54-90% of patients Recurrence of leukoplakia at cessation of Recurrence of leukoplakia at cessation of

treatment - 50% of patientstreatment - 50% of patients

Chemoprevention Retinoids - Isotretinoin, Interferon -2a, and Vitamin E

Stage III and IV - 24 month median follow-upStage III and IV - 24 month median follow-up Sixteen percent (7/45) patients - died Sixteen percent (7/45) patients - died Twenty percent (9/45) - progressive disease.Twenty percent (9/45) - progressive disease. Second primary tumorsSecond primary tumors

One episode acute promyelocytic leukemiaOne episode acute promyelocytic leukemia 5-year progression-free survival - 80%5-year progression-free survival - 80% 5-year overall survival - 81.3% 5-year overall survival - 81.3% Historical 5-year overall survival for advanced Historical 5-year overall survival for advanced

squamous cell carcinoma of head and neck - 40%squamous cell carcinoma of head and neck - 40%

Chemoprevention Retinoids Acute toxicityAcute toxicity

Dry conjunctival and oral mucous membranesDry conjunctival and oral mucous membranes CheilitisCheilitis Skin desquamationSkin desquamation HypertriglyceridemiaHypertriglyceridemia Bone tendernessBone tenderness Arthralgias, and myalgiasArthralgias, and myalgias

Chronic toxicities Chronic toxicities Hepatotoxicity and bone remodelingHepatotoxicity and bone remodeling TeratogenicityTeratogenicity

Intra-arterial Chemotherapy

Principal determinant of a drug's therapeutic Principal determinant of a drug's therapeutic advantage - ratio of total body clearance to advantage - ratio of total body clearance to regional exchange rateregional exchange rate

Maximum cell kill - when tumor exposure Maximum cell kill - when tumor exposure to a high concentration of drug is optimized to a high concentration of drug is optimized


Factors to be considered when choosing a drugFactors to be considered when choosing a drug

1.1. Concentration, not time of exposureConcentration, not time of exposure

2.2. Drug should be deactivated in the systemic Drug should be deactivated in the systemic circulationcirculation

3.3. High tissue extractionHigh tissue extraction

4.4. No requirement of activation in the liver.No requirement of activation in the liver.


Stage III/IV - 213 patientsStage III/IV - 213 patients Weekly intraarterial infusion of cisplatin, Weekly intraarterial infusion of cisplatin,

simultaneous intravenous thiosulfate, and external simultaneous intravenous thiosulfate, and external beam radiotherapy beam radiotherapy

Complete tumor response in the primary sites - Complete tumor response in the primary sites - 80%80%

Complete tumor response in regional sites - 61%Complete tumor response in regional sites - 61% 5-year survival was 54%5-year survival was 54% Six treatment-related deaths occurredSix treatment-related deaths occurred

New Trends in Chemotherapy Three Drug Regimen: Docetaxel, cisplatin, and Three Drug Regimen: Docetaxel, cisplatin, and

fluorouracil induction chemotherapyfluorouracil induction chemotherapy Monoclonal Ab against Epidermal Growth Factor Monoclonal Ab against Epidermal Growth Factor

Receptor (Cetuximab)Receptor (Cetuximab) Intratumoral cisplatin/epinephrine injectable gelIntratumoral cisplatin/epinephrine injectable gel Farnesyl transferase inhibitors Farnesyl transferase inhibitors Adenovirus-mediated p53 gene therapy (with Adenovirus-mediated p53 gene therapy (with

docetaxel)docetaxel) Fas ligand (FasL) gene therapy Fas ligand (FasL) gene therapy Adenovirus-mediated retinoblastoma (Ad-RB94) Adenovirus-mediated retinoblastoma (Ad-RB94)

gene therapy gene therapy

New Trends in Chemotherapy Three Drug Regimen: Docetaxel, cisplatin, and fluorouracil induction chemotherapy (three cycles)

95% of patients in study were Stage IV95% of patients in study were Stage IV Biopsy - negative for cancer in 64 patients (89%) Biopsy - negative for cancer in 64 patients (89%)

and positive in 8 patients (11%)and positive in 8 patients (11%) 25% (2/8) patients died of disease in positive 25% (2/8) patients died of disease in positive

biopsy group vs 4% (3/64) patients in the negative biopsy group vs 4% (3/64) patients in the negative biopsy group at 2 years follow-upbiopsy group at 2 years follow-up

Overall 2- and 5-year progression-free survival is Overall 2- and 5-year progression-free survival is currently projected at 85% and 85%, respectivelycurrently projected at 85% and 85%, respectively

Overall 2- and 5-year survival, at 95% and 90%, Overall 2- and 5-year survival, at 95% and 90%, respectivelyrespectively

Pathological complete response rate - 89%Pathological complete response rate - 89%

New Trends in ChemotherapyCetuximab - Monoclonal Ab against Epidermal

Growth Factor Receptor EGFR expression ~ 90% of specimensEGFR expression ~ 90% of specimens Two groupsTwo groups

213 patients - high-dose radiotherapy alone213 patients - high-dose radiotherapy alone 211 patients - high-dose radiotherapy plus weekly 211 patients - high-dose radiotherapy plus weekly

cetuximab cetuximab Locoregional controlLocoregional control

Cetuximab plus radiotherapy - 24.4 monthsCetuximab plus radiotherapy - 24.4 months Radiotherapy alone - 14.9 months Radiotherapy alone - 14.9 months

Overall survival (over 54 months)Overall survival (over 54 months) Cetuximab plus radiotherapy - 49 monthsCetuximab plus radiotherapy - 49 months Radiotherapy alone - 29.3 months Radiotherapy alone - 29.3 months

No effect on distant metastasesNo effect on distant metastases

New Trends in ChemotherapyCetuximab - Monoclonal Ab against Epidermal

Growth Factor Receptor Authors did not compare the combination of Authors did not compare the combination of

cetuximab plus radiotherapycetuximab plus radiotherapy with the current standard with the current standard of care (platinum-based chemoradiotherapy)of care (platinum-based chemoradiotherapy)

Authors did not administer the radiotherapy uniformlyAuthors did not administer the radiotherapy uniformly

among all patientsamong all patients Survival benefit of cetuximab was evident for Survival benefit of cetuximab was evident for

oropharyngeal cancer (> half patients) oropharyngeal cancer (> half patients) No improvement in survival in patients with No improvement in survival in patients with

hypopharyngealhypopharyngeal or laryngeal canceror laryngeal cancer Hyperfractionated radiotherapy is effective,Hyperfractionated radiotherapy is effective, but is but is

associated with a high rate of esophageal stenosisassociated with a high rate of esophageal stenosis

New Trends in ChemotherapyFarnesyltransferase inhibitors

~ 27% oral cavity cancers - ras gene mutation~ 27% oral cavity cancers - ras gene mutation Blocking the prenylation of Ras proteins in cell Blocking the prenylation of Ras proteins in cell

lines with Ras activated by mutations or lines with Ras activated by mutations or receptor signaling resulted in radiation receptor signaling resulted in radiation sensitization of tumor cells sensitization of tumor cells in vitroin vitro and and in vivoin vivo

Combination with paclitaxel - cytotoxic effects Combination with paclitaxel - cytotoxic effects for head and neck squamous cell carcinomafor head and neck squamous cell carcinoma

New Trends in ChemotherapyGene Therapy

Adenovirus-mediated p53 gene therapy (with docetaxel)Adenovirus-mediated p53 gene therapy (with docetaxel) Mutations of p53 - 45-70% of head and neck squamous Mutations of p53 - 45-70% of head and neck squamous

cell cancer patientscell cancer patients Ad-p53 - induced apoptosis of cancer cells and reduced Ad-p53 - induced apoptosis of cancer cells and reduced

tumor growth in mouse xenograft modelstumor growth in mouse xenograft models Ad-p53 combined with cisplatin, doxorubicin, 5-Ad-p53 combined with cisplatin, doxorubicin, 5-

fluorouracil, methotrexate, or etoposide inhibited cell fluorouracil, methotrexate, or etoposide inhibited cell proliferation more effectively than chemotherapy aloneproliferation more effectively than chemotherapy alone

Docetaxel enhanced Ad-p53 transduction and increased Docetaxel enhanced Ad-p53 transduction and increased expression of exogenous p53 gene transfer, apoptosis, expression of exogenous p53 gene transfer, apoptosis, and antitumor mechanismsand antitumor mechanisms

New Trends in Chemotherapy Gene therapy

Adenovirus-mediated retinoblastoma (Ad-RB94) gene Adenovirus-mediated retinoblastoma (Ad-RB94) gene therapy therapy

Reduction in tumor size Reduction in tumor size Cell cycle arrest in the G2-M phase and increased Cell cycle arrest in the G2-M phase and increased

levels of apoptosis occurred in tumor cells treated levels of apoptosis occurred in tumor cells treated with Ad-RB94with Ad-RB94

Telomerase activity decreased significantly Telomerase activity decreased significantly Good candidate for adjuvant therapy with radiation or Good candidate for adjuvant therapy with radiation or

chemotherapy, as tumor cells are most sensitive to chemotherapy, as tumor cells are most sensitive to radiation or cytotoxic drug in this cell cycle phase.radiation or cytotoxic drug in this cell cycle phase.

Conclusion

Chemotherapy in Head and Neck Cancer Chemotherapy in Head and Neck Cancer has numerous diverse optionshas numerous diverse options

Many new therapies are in developmentMany new therapies are in development

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