Chemotherapy and Why we Leave it to The Oncologists

1
Chemotherapy and Why we Leave it to The
Oncologists

• Vanessa Rothholtz, M.D., M.Sc.
• Department of Otolaryngology - Head and Neck
  Surgery
• UCI Medical Center

2
Introduction

• Describe the cell cycle and the phase that is
  affected by chemotherapeutic agents
• Classification, Mechanism of Action and Side
  Effects of common agents used in the treatment of
  squamous cell carcinoma
• Definition of the terms induction concurrent
  neoadjuvant and adjuvant in relation to
  chemotherapy
• Role of chemotherapy in the management of head
  and neck cancer as a single modality treatment
• Role of combination chemotherapy in the
  management of head and neck cancer treatment

3
Introduction

• Organ preservation VA Larynx Study, Duke
  Protocol
• Side effects of chemotherapeutic agents used in
  treatment of head and neck cancer
• Measures that exist to reduce side effects
• Concurrent chemotherapy combined with radiation.
  Additional toxicity.
• Chemoprevention with Retinoids
• Intra-arterial chemotherapy for head and neck
  cancer
• New chemotherapeutic agents

4

• G1Phase Growth.
• S Phase DNA-synthesis and replication.
• G2 Phase the cell checks that DNA-replication is
  completed and prepares for cell division.
• M Phase The chromosomes are separated (mitosis,
  M) and the cell divides into two daughter cells.

5
Chemotherapeutic Agents and the Cell Cycle
From Milas L, Mason KA, Liao Z, Ang KK
Chemoradiotherapy emerging treatment improvement
strategies. Head Neck. 2003 Feb25(2)152-67
6
Classification of Chemotherapeutic Agents

• Alkylating Agents Cisplatin, Carboplatin,
  Melphalan
• Antimetabolites Methotrexate, 5-FU
• Antitumor Antibiotics Doxorubicin, Adriamycin,
  Bleomycin, Mitomycin-C, Ifosfamide
• Alkaloids Vincristine,Vinblastine, Vinorelbine
• Taxanes Paclitaxel and docetaxel.
• Nucleoside analogues Gemcitabine, Fludarabine,
  Cytosine arabinoside
• Nitrosoureas BCNU, CCNU
• Topoisomerase inhibitors Topotecan, Etoposide
• Hydroxyurea

7
Classification of Chemotherapeutic Agents

• Alkylating Agents 
• Substitution reactions, cross-linking reactions
  or strand-breaking reactions of DNA.
• Alter the information coded in the DNA molecule
  resulting in inhibition of or inaccurate DNA
  replication with resultant mutation or cell
  death.

8
Classification of Chemotherapeutic
AgentsAlkylating Agents Mechanism of Cisplatin
/ Carboplatin

• Inorganic metal coordination complex
• Bifunctional alkylating agent binding to DNA to
  cause interstrand and intrastrand cross-linking.
• Binds to nuclear and cytoplasmic proteins.
• Resistance is believed to develop through
  increased metabolic inactivation

9
Classification of Chemotherapeutic
AgentsAlkylating Agents Adverse Effects of
Cisplatin / Carboplatin

• Renal dysfunction
• Hematologic toxicity - neutropenia,
  thrombocytopenia
• Bone Marrow Suppression - acute hemolytic anemia.
• Hypomagnesemia
• Ototoxicity
• Peripheral Neuropathy -neurotoxicity

10
Classification of Chemotherapeutic Agents

• Antimetabolites. 
• Exerts cytotoxic effects by virtue of structural
  or functional similarity to naturally occurring
  metabolites involved in nucleic acid synthesis.
• Inhibits critical enzymes involved in nucleic
  acid synthesis.
• Incorporates into the nucleic acid and produces
  incorrect codes.
• Resulting in inhibition of DNA synthesis and
  ultimate cell death.

11
Classification of Chemotherapeutic
AgentsAntimetabolites Mechanism of Methotrexate

• Folic acid analog that is S-phase specific
• Binds to the enzyme dihydrofolate reductase, that
  blocks the reduction of dihydrofolate to
  tetrahydrofolic acid which is necessary for the
  synthesis of thymidylic acid and purine.
• Interrupts the synthesis of DNA, RNA, and
  protein.
• Mechanisms for resistance to methotrexate
  include
• Selection of cells with decreased transport of
  methotrexate into cells
• Increased dihydrofolate reductase activity.

12
Classification of Chemotherapeutic
AgentsAntimetabolites Adverse Effects of
Methotrexate

• Mild stomatitis
• Myelosuppression
• Confluent mucositis
• Pancytopenia
• Liver function abnormalities
• Exfoliative maculopapular rash
• Renal dysfunction

13
Classification of Chemotherapeutic
AgentsAntimetabolites Mechanism of
5-Fluorouracil

• Fluorinated pyrimidine similar to uracil
• 5-FU competes for the enzyme thymidylate
  synthetase by displacing uracil.
• Inhibits the formation of thymidine, an essential
  factor in DNA synthesis

14
Classification of Chemotherapeutic
AgentsAntimetabolites Adverse Effects of
5-Fluorouracil

• Myelosuppression
• Neutropenia
• Thrombocytopenia occurring at 1 or 2 weeks.
• Nausea, vomiting, and diarrhea
• Stomatitis
• Alopecia
• Hyperpigmentation
• Maculopapular rash

15
Classification of Chemotherapeutic Agents

• Anti-tumor Antibiotics. 
• Group of related anti-microbial compounds
  produced by Streptomyces species in culture.
• Affect the structure and function of nucleic
  acids by
• Intercalation between DNA base pairs (doxorubicin
  - adriamycin)
• DNA strand fragmentation (bleomycin)
• Cross-linking of DNA (mitomycin, ifosfamide)

16
Classification of Chemotherapeutic Agents

• Alkaloids.
• Bind to free tubulin dimers
• Disrupt the balance between microtubule
  polymerization and depolymerization, resulting in
  the net dissolution of microtubules, destruction
  of the mitotic spindle, and arrest of cells in
  metaphase.

17
Classification of Chemotherapeutic Agents

• Taxanes.
• Disrupt equilibrium between free tubulin and
  microtubules causing stabilization of ordinary
  cytoplasmic microtubules and the formation of
  abnormal bundles of microtubules.

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Single Agent ChemotherapyCriteria for Response
19
Single Agent Chemotherapy

•  

20
Induction Chemotherapy

• Chemotherapy before surgery or radiotherapy
• Promotes regression of tumor
• Enhances local-regional therapy via sensitization
• Identifies patients who might be candidates for a
  more conservative surgical approach
• Treats micrometastatic disease in hopes of
  reducing distant failure rates, which can be 40
  or greater with conventional local-regional
  surgical/radiation approaches
• Improves the ability to identify responding
  tumors that might benefit from adjuvant
  chemotherapy

21
Concurrent Chemotherapy

• Used primarily in patients with unresectable
  disease to improve local and regional control
• Interaction between cytotoxic drugs and radiation
  that results in additive or synergistic
  enhancement due to
• Inhibition of DNA repair
• Redistribution of cells in sensitive phases of
  the cell cycle
• Promotion of oxygenation of anoxic tissues

22
Neoadjuvant Chemotherapy

• The application of chemotherapy prior to any
  other anticancer therapy
• Provides earlier exposure of potential
  micrometastases to chemotherapy than is achieved
  with the standard adjuvant approach
• Objective response to chemotherapy in the primary
  lesion provides important in vivo evidence that
  the therapy being used has anti-tumor activity
  and suggests that the tumor at remote subclinical
  sites will be sensitive as well

23
Adjuvant Chemotherapy

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

24
Combination Chemotherapy

• Cisplatin and continuous infusion Bleomycin - 71
  overall response rate with complete responses
  noted in 21 of patients (Wittes, et al.)
• Neoadjuvant cisplatin with infusion
  5-fluorouracil (5-FU) - 88 overall response rate
  with complete response rate of 54
• 120-hour 96-hour infusion 5-fluorouracil
• Three to five cycles two cycles
• Metanalysis by Browman and Cronin found a more
  conservative statistic with overall response
  rates of cisplatin and 5-FU to be 32, and the
  complete response rate ranging from 5 to 15

25
ChemoradiationMechanism of Interaction

• Increase in initial radiation damage
• Inhibition of cellular repair
• Cell cycle effects
• Elimination of radioresistant S-phase cells
• Arrest in radiosensitive G2 or M
• Counteracting radioresistance caused by hypoxic
  cells
• Elimination of hypoxic cells
• Increase in tumor oxygenation through cell loss
• Overcoming accelerated repopulation

26
Chemoradiation Trials

• Numerous Trials with
• conflicting / equivocal results

27
Organ Preservation

• Hanna et al. - 2004
• Duke Chemoradiation Protocol - 1998
• VA study - 1991
• Efficacy
• Toxic Effects
• Limitations

28
Organ PreservationHanna - Demographics

• Ninety-six (76) men
• Thirty-one (24) women
• Average age at diagnosis - 62 years (37-85 years)
• Primary tumor site
• Oropharynx 58 patients (46)
• Larynx 36 patients (28)
• Hypopharynx 20 patients (16)
• Oral cavity 10 patients (8)
• Other 3 patients (2)
• Ninety-one (91) stage III or IV disease

29
Organ PreservationHanna - Treatment

• Standard fractionation radiotherapy (total dose
  of 66-72 Gy)
• At least 2 cycles of cisplatin and fluorouracil
  concurrently with radiotherapy.
• Of the 127 patients, 44 also received an
  additional 2 cycles of neoadjuvant chemotherapy
  before starting concurrent chemoradiotherapy
• Patients with less than a complete response to
  chemoradiotherapy underwent salvage surgery

30
Organ PreservationHanna - Outcomes

• Complete response at the primary tumor site - 109
  patients (86)
• Local disease control - 113 patients (89)
• Organ preservation - 102 patients (80).
• Clinical N disease - 83/127 patients
• Complete clinical response - 57 patients (69)
• N1 - 93
• N2 - 62
• N3 - 47
• Regional disease control - 76/83 (92)
• Distant metastasis - 18 patients (14)

31
Organ PreservationHanna - Outcomes

• Disease-specific survival 72
• Overall survival 57
• Severe Side Effects
• Severe (grade 3 or 4) mucositis - 33
• Neutropenia - 25
• Death - 2 patients

32
Organ PreservationDuke Protocol
33
Organ PreservationDuke Protocol -
Demographics/Treatment

• Stage III/IV and Base of Tongue T2N0
• Chemotherapy (fluorouracil and cisplatin) was
  administered at weeks 1 and 6 followed by two
  additional cycles of cisplatin and fluorouracil
  after the completion of all local therapy, with
  the cisplatin again divided into five daily
  boluses, and the dose increased in cycle 3 and in
  cycle 4.

34
Organ PreservationDuke Protocol - Overall
Survival
35
Organ PreservationDuke Protocol - Disease Free
Survival
36
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Organ PreservationDuke Protocol - Randomization?

• Imbalances in the two treatment groups
• More patients with advanced nodal disease (N2 or
  N3) in hyperfractionation group than in the
  combined-treatment group (63 vs. 45)
• More patients with hypopharynx as a primary site
  (which is associated with a less favorable
  result) in the combined-treatment group and more
  patients with oropharynx (tonsil and base of
  tongue) as a primary site (which is associated
  with a more favorable result) in the
  hyperfractionation group

38
The VA Study

• Patients Stage III or IV laryngeal SCCA
• Two groups
• Induction chemotherapy (Cisplatin and 5-FU three
  cycles) followed by definitive radiation therapy
  (6600 to 7600 cGy)
• Conventional laryngectomy and post-operative
  radiation

39
The VA StudyOutcomesCauses of Death According
to Treatment Assignment
40
The VA StudyOutcomesPatterns of Tumor
Recurrence According to Treatment Group
41
The VA StudyOutcomesSalvage Laryngectomy

• For persistent disease before radiation therapy
  or within three months afterward - 29 (48/166)
• For later recurrent disease - 7 (11/166)
• Glottic cancers Supraglottic cancers
• Fixed vocal cords Mobile cords
• Gross invasion of cartilage No invasion
• Stage IV cancers Stage III (44 vs. 29)
• T4 smaller primary tumors (56vs. 29)

42
Nasopharyngeal Carcinoma

• 147 randomized patients - Stage III or IV
• Radiotherapy alone vs. Cisplatin (100 mg/m2 days
  1, 22, and 43) during radiotherapy followed by
  adjuvant chemotherapy with cisplatin and 5-FU
  (three cycles)
• 3-year survival time (78 vs 47)
• Progression-free survival time (69 vs 24)

43
Side Effects

• Marked increase in acute toxicity
• Mucositis
• Dermatitis
• Increased risk of infection
• Poor nutritional intake
• Interruption of radiotherapy
• Chemotherapy dose reductions

44
Side Effects
45
Side Effects Acute Mucositis
46
Side EffectsAcute Mucositis

• Long-term dysphagia
• Thick, ropey, copious oropharyngeal
• Secretions interfere with swallowing, cause
  gagging and regurgitation, and predispose to
  aspiration
• The limiting factor

47
Side EffectsAcute Mucositis and Dysphagia

• Patients with nasogastric feeding tubes may have
  less long-term dysphagia, feeding tube duration,
  and need for pharyngoesophageal dilation
• Nothing-by-mouth (NPO) intervals as short as 2
  weeks have been shown to predict poor swallowing
  outcomes

48
Side EffectsAcute Mucositis - Treatment

• Polymyxin E, Tobramycine, and Amphotericin B
• Granulocyte macrophage-colony-stimulating factor,
  Granulocyte colony-stimulating factor
  (GM-CSF/G-CSF)
• Oral cooling
• Amifostine - Ethyol - Organic thiophosphate. It
  has a higher alkaline phosphatase activity,
  higher pH and vascular permeation of normal
  tissues
• Palmifermin - Recombinant human keratinocyte
  growth factor

49
Side EffectsAcute Mucositis - Amifostine

• Patients
• Radiation therapy twice daily - 1.6-gray (Gy)
  fractions up to a total of 70.4 Gy over 6.5 weeks
• Paclitaxel 60 mg/m2 once weekly starting on Day 1
• Number of doses of paclitaxel increased from
  three to six
• Amifostine - 400 mg/m2 IV on Days 1-5, 8, 29-33,
  and 36
• Amifostine Paclitaxel
• Additional dose of treatment (5 vs. 4)

50
Side EffectsAcute Mucositis - Palmifermin

• 106 patients - palifermin (60 µg/kg/day)
• Incidence of grade 3 or 4 oral mucositis - 63
• Duration - 3 days (0 to 22)
• Less soreness of mouth, less use of morphine and
  TPN
• 106 patients - placebo
• Incidence of grade 3 or 4 oral mucositis - 98
• Duration - 9 days (0 to 27)
• Grade 4 oral mucositis - 62
• Adverse events - Rash, pruritus, erythema, mouth
  and tongue disorders, and taste alteration

51
Side EffectsNeuropathy and Vitamin E

• Thirty-one patients
• Six courses of cumulative cisplatin, paclitaxel,
  or both
• Group I (n 16) - oral vitamin E at a daily dose
  of 600 mg/day during chemotherapy and 3 months
  after its cessation
• Neurotoxicity - occurred in 4/16 (25) patients
• Group II (n 15) - no supplementation
• Neurotoxicity - occurred in 11/15 (73.3) patients

52
Chemoprevention Bioadjuvant Therapy

• Second primary malignancies develop at a rate of
  3 to 4 per year in patients who are curatively
  treated for an early stage head and neck squamous
  cell cancer

53
Chemoprevention Retinoids

• Retinoids have been shown to modify genomic
  expression at the level of messenger RNA
  synthesis and to regulate transcription of
  specific genes
• Prevent malignant transformation of dysplastic
  leukoplakia lesions
• Prevent second primary cancers

54
Chemoprevention Retinoids

• Retinoid use in Oral Leukoplakia
• Complete response - 10-27 of patients
• Partial response - 54-90 of patients
• Recurrence of leukoplakia at cessation of
  treatment - 50 of patients

55
Chemoprevention Retinoids - Isotretinoin,
Interferon ?-2a, and Vitamin E

• Stage III and IV - 24 month median follow-up
• Sixteen percent (7/45) patients - died
• Twenty percent (9/45) - progressive disease.
• Second primary tumors
• One episode acute promyelocytic leukemia
• 5-year progression-free survival - 80
• 5-year overall survival - 81.3
• Historical 5-year overall survival for advanced
  squamous cell carcinoma of head and neck - 40

56
Chemoprevention Retinoids

• Acute toxicity
• Dry conjunctival and oral mucous membranes
• Cheilitis
• Skin desquamation
• Hypertriglyceridemia
• Bone tenderness
• Arthralgias, and myalgias
• Chronic toxicities
• Hepatotoxicity and bone remodeling
• Teratogenicity

57
Intra-arterial Chemotherapy

• Principal determinant of a drug's therapeutic
  advantage - ratio of total body clearance to
  regional exchange rate
• Maximum cell kill - when tumor exposure to a high
  concentration of drug is optimized

58
Intra-arterial Chemotherapy

• Factors to be considered when choosing a drug
• Concentration, not time of exposure
• Drug should be deactivated in the systemic
  circulation
• High tissue extraction
• No requirement of activation in the liver.

59
Intra-arterial Chemotherapy

• Stage III/IV - 213 patients
• Weekly intraarterial infusion of cisplatin,
  simultaneous intravenous thiosulfate, and
  external beam radiotherapy
• Complete tumor response in the primary sites -
  80
• Complete tumor response in regional sites - 61
• 5-year survival was 54
• Six treatment-related deaths occurred

60
New Trends in Chemotherapy

• Three Drug Regimen Docetaxel, cisplatin, and
  fluorouracil induction chemotherapy
• Monoclonal Ab against Epidermal Growth Factor
  Receptor (Cetuximab)
• Intratumoral cisplatin/epinephrine injectable gel
• Farnesyl transferase inhibitors
• Adenovirus-mediated p53 gene therapy (with
  docetaxel)
• Fas ligand (FasL) gene therapy
• Adenovirus-mediated retinoblastoma (Ad-RB94) gene
  therapy

61
New Trends in Chemotherapy Three Drug Regimen
Docetaxel, cisplatin, and fluorouracil induction
chemotherapy (three cycles)

• 95 of patients in study were Stage IV
• Biopsy - negative for cancer in 64 patients (89)
  and positive in 8 patients (11)
• 25 (2/8) patients died of disease in positive
  biopsy group vs 4 (3/64) patients in the
  negative biopsy group at 2 years follow-up
• Overall 2- and 5-year progression-free survival
  is currently projected at 85 and 85,
  respectively
• Overall 2- and 5-year survival, at 95 and 90,
  respectively
• Pathological complete response rate - 89

62
New Trends in ChemotherapyCetuximab - Monoclonal
Ab against Epidermal Growth Factor Receptor

• EGFR expression 90 of specimens
• Two groups
• 213 patients - high-dose radiotherapy alone
• 211 patients - high-dose radiotherapy plus weekly
  cetuximab
• Locoregional control
• Cetuximab plus radiotherapy - 24.4 months
• Radiotherapy alone - 14.9 months
• Overall survival (over 54 months)
• Cetuximab plus radiotherapy - 49 months
• Radiotherapy alone - 29.3 months
• No effect on distant metastases

63
New Trends in ChemotherapyCetuximab - Monoclonal
Ab against Epidermal Growth Factor Receptor

• Authors did not compare the combination of
  cetuximab plus radiotherapy with the current
  standard of care (platinum-based
  chemoradiotherapy)
• Authors did not administer the radiotherapy
  uniformly among all patients
• Survival benefit of cetuximab was evident for
  oropharyngeal cancer ( half patients)
• No improvement in survival in patients with
  hypopharyngeal or laryngeal cancer
• Hyperfractionated radiotherapy is effective, but
  is associated with a high rate of esophageal
  stenosis

64
New Trends in ChemotherapyFarnesyltransferase
inhibitors

• 27 oral cavity cancers - ras gene mutation
• Blocking the prenylation of Ras proteins in cell
  lines with Ras activated by mutations or receptor
  signaling resulted in radiation sensitization of
  tumor cells in vitro and in vivo
• Combination with paclitaxel - cytotoxic effects
  for head and neck squamous cell carcinoma

65
New Trends in ChemotherapyGene Therapy

• Adenovirus-mediated p53 gene therapy (with
  docetaxel)
• Mutations of p53 - 45-70 of head and neck
  squamous cell cancer patients
• Ad-p53 - induced apoptosis of cancer cells and
  reduced tumor growth in mouse xenograft models
• Ad-p53 combined with cisplatin, doxorubicin,
  5-fluorouracil, methotrexate, or etoposide
  inhibited cell proliferation more effectively
  than chemotherapy alone
• Docetaxel enhanced Ad-p53 transduction and
  increased expression of exogenous p53 gene
  transfer, apoptosis, and antitumor mechanisms

66
New Trends in Chemotherapy Gene therapy

• Adenovirus-mediated retinoblastoma (Ad-RB94) gene
  therapy
• Reduction in tumor size
• Cell cycle arrest in the G2-M phase and increased
  levels of apoptosis occurred in tumor cells
  treated with Ad-RB94
• Telomerase activity decreased significantly
• Good candidate for adjuvant therapy with
  radiation or chemotherapy, as tumor cells are
  most sensitive to radiation or cytotoxic drug in
  this cell cycle phase.

67
Conclusion

• Chemotherapy in Head and Neck Cancer has numerous
  diverse options
• Many new therapies are in development

68
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