Chemotherapy For H

1
Chemotherapy For HN SCC Past, Present and Future

• Charles Gawthrop M.D.
• Faculty Discussant
• Jason Newman M.D.

2
The Past

• 40,000 New cases of SCCHN each year in USA
• 2/3 Present with locally advanced lesions (T3 or
  T4)
• 5 year survival lt30

3
The Past

• Classical chemotherapy is directed at metabolic
  sites essential to cell replication
• Tumor Cells Replicate more frequently than normal
  cells
• However, currently available chemotherapy does
  not specifically recognize neoplastic cells
• Highest morbidities in rapidly dividing cells
  bone marrow, GI mucosa, and hair cells

4
Methotrexate

• Most widely used cytotoxic for H N cancer prior
  to 19781.
• Structural analog of folic acid, binds to and
  inhibits dihyrofolate reductase.
• Decreases intracellular folate co-enzymes, which
  decreases production of thymidilic acid
  (precursor to adenine and guainine) and
  eventually depressed DNA/RNA synthesis and cell
  death.

5
Methotrexate
6
Methotrexate

• Toxicities
• Myelosupression, mucocitis, alopecia, N/V and
  Diarrhea Most common
• Renal Toxicity in Higher Doses

7
5 - Fluorouracil

• Antimetabolite - Like Methotrexate deprives cells
  of essential precursors of DNA synthesis
• Pyrimidine analog which has a stable flourine
  atom in place of hydrogen at position 5 of the
  uracil ring.

8
5-FU

• Converted to Fluoride-deoxyuridine monophosphate
  (FdUMP) which competes with dUMP for thymidilate
  synthase, leading to a lack of thymidine,
  imbalanced cell growth and death.

9
5-FU

• Side Effects
• MUCOCITIS
• Other side effects include bone marrow
  supression, N/V, alopecia and anorexia

10
Cisplatin

• Cisdiamminedichlorplatinum (CDDP)
• Approved by USDA in 1978.
• Binds to Guanine on DNA, forming inter and
  intra-strand crosslinks, inhibiting DNA synthesis.

11
Cisplatin

• Side Effects
• Severe Nausea and Vomiting up to 5 days after
  administration
• Nephrotoxicity- Usually the dose limiting
  toxicity
• Ototoxicity High Frequency Hearing Loss,
  Tinnitus
• Neurotoxicity Paresthesias, Loss of
  Proprioception

12
Carboplatin

• Mechanism is similar to that of Cisplatin
• Less Effective
• Lower Toxicity

13
Multi Agent Chemotherapy

• In Mid 1980s a number of RCT controlled trials
  compared the then available combinations of
  chemotherapeutics.
• Cisplatin as a single agent is not superior to
  Methotrexate in terms of response or survival1
• Multi-agent chemotherapy in general is associated
  with higher response rates than single agent
  alone
• Platinum containing combination regimens have the
  highest response rates.

14
Multi Agent Chemotherapy

• Jacobs et al2 1992 Compared Cisplatin and 5 FU
  alone and in combination. Response rates were 32
  (Cisplatin 5FU), 17 (Cisplatin), and 13
  (5FU).
• Higher Toxicity in Combination
• Median Survival (6months) same for all treatment
  arms
• Clavel et al.3 1994 Compared Cisplatin vs
  Cisplatin 5FU in 382 patients with metastatic
  or recurrent SCC of the H N
• Higher Response Rates and Longer time to
  progression in combination
• Median survival 7.3 months in both arms

15
The Taxanes

• Paclitaxel (Taxol) and Docetaxel (Taxotere)
• Isolated in 1960s from the bark of the pacific
  Yew tree (Taxus brevifolia) and introduced in
  1990s
• Binds to the B subunit of tubulin, and stabilizes
  microtubules, interrupting mitosis and leading to
  cell death.

16
The Taxanes

• Side Effects
• NEUTROPENIA Usually Dose Limiting
• Hypersensitivity (dyspnea, urticaria,
  hypotension)
• Peripheral Neuropathy, Alopecia, Bradycardia

17
The Taxanes

• Several Studies of Taxane Cisplatin with
  response rates of 27 - 53
• Gibson et al.4 2005 218 Patients. Compared
  Cisplatin and 5FU vs. Cisplatin and Taxol.
• Response rates and Median Survival were virtually
  identical with higher number of high grade
  toxicities in Cisplatin 5 FU Group
• Triple Agent Protocols including Docetaxol,
  Cisplatin, and 5FU (TPF) have shown response
  rates approaching 60, with median survival of 6
  9 months.1 However no improvement in 1 year
  survival and increased toxicity. To date, no
  controlled trials

18
Chemotherapy for Curable Disease

• Induction or Neoadjuvant Chemotherapy
• Concomitant Chemotherapy
• Post Treatment or Adjuvant Chemotherapy

19
Concomitant Chemotherapy
20
Concomitant Chemotherapy

• Theoretical Benefits of Chemo-XRT
• Inhibiting repair of lethal and sublethal damage
  induced by radiotherapy
• Radiosensitizing hypoxic cells
• Reducing tumor burden, leading to an improved
  blood supply
• Redistributing tumor cells to a more
  radiosensitive cell cycle phase
• Inducing apoptosis

21
Concomitant Chemotherapy

• Meta-Analysis of Chemotherapy on Head and Neck
  Cancer (Pignon et al.) 20005
• Meta-analysis of gt10,000 patients in 63 clinical
  trials
• Chemo-XRT vs. XRT alone associated with absolute
  survival benefit of 8 at 5 years
• Intergroup RTOG 91-11 (Forastiere et al.) 20036
• 547 Patients with stage III or IV resectable
  laryngeal cancer. Randomized to Induction Chemo
  XRT vs. Chemo-XRT vs. XRT alone
• 43 absolute reduction in laryngectomy rate with
  Chemo-XRT
• 8 vs. 16 rate of distant metastasis
• No change in overall survival

22
Neoadjuvant Chemotherapy
23
Neoadjuvant Chemotherapy

• Theoretically should reduce possibility of
  distant metastasis, and decrease tumor burden
  while patient is healthy, thus leading to
  improved disease free survival.
• However Numerous studies over 2 decades showed
  no benefit in survival when compared with local
  treatment. Though some reported a decrease in
  distant metastases

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Neoadjuvant Chemotherapy

• GSSTC (Paccagnella et al.) 19948. 237 Patients
  with stage III and IV SCC of the head and neck.
  Cisplatin, 5FU followed by local tx vs. local tx
  alone.
• Increase in 10 year survival
• GETTEC (Domenge et al.) 20009. 318 patients with
  curable disease of oropharynx randomized to chemo
  followed by local treatment vs. local treatment
  alone.
• Overall Median Survival 5.1 years vs. 3.3 years
  with Chemo
• No change in locoregional control or distant
  metastases

26
Neoadjuvant Chemotherapy

• Meta-Analysis of Chemotherapy on Head and Neck
  Cancer5
• In the initial study, induction chemotherapy was
  associated with only a 2 survival benefit at 5
  years - not statistically significant
• However in a subset analysis including only
  cisplatin-5FU induction regimens there was a
  significant 5 absolute survival benefit.

27
Neoadjuvant Chemotherapy

• TAX 323 (Vermorken et al. 2004)10 358 patients
  with locally advanced and unresectable HNSCC.
  Induction chemo with cisplatin 5FU (PF) or
  cisplatin/5FU/docetaxel (TPF) All patients
  received post chemo XRT
• Overall response rate with TPF was significantly
  improved 68 vs. 54
• Both progression free and overall survival times
  were longer with TPF

28
Neoadjuvant Chemotherapy

• So why give induction chemotherapy another
  chance?11,12
• Previous studies included suboptimal chemotherapy
  regimens
• Newer triple agent chemotherapy with Taxane
• Chemotherapy followed by Chemo-XRT

29
Adjuvant Chemotherapy
30
Adjuvant Chemotherapy

• Post operative XRT has been the standard approach
  for high risk HN SCC since first pioneered by
  Fletcher and Evers in the early 1970s.
• However, the few randomized studies of post
  operative chemotherapy in the 1990s yielded
  disappointing results.

31
Adjuvant Chemotherapy

• Intergroup Study 0034 (Al-Sarraf et al 1997)13.
  447 patients, complete resection with post op XRT
  alone vs. resection XRT Chemo.
• No difference in overall survival
• However, subgroup of patients at higher risk
  (malignant cells in 2 or more lymph nodes,
  extracapsular spread, microscopic involvement of
  margins), were more likely to benefit both in
  terms of tumor control and survival
• Bachaud et al.14,15 1996 83 patients. Surgery
  followed by XRT or Chemoradiation.
• Chemoradiation group had lower locoregional
  failure

32
Adjuvant Chemotherapy

• EORTC Study (Bernier et al. 2004)16 334 patients
  with high risk head and neck tumors randomly
  assigned to post op XRT vs. post op Chemo-XRT
• High Risk Vascular invasion, Perineural
  invasion, Stage III/IV disease, Microscopically
  Margins, extracapsular spread
• Progression free survival of 55 vs. 23 months
• Locoregional recurrence of 31 vs. 18
• No Significant change in toxicity
• RTOG Trial (Cooper et al. 2004)17 459 patients
  with High risk SCC randomized to post op XRT vs.
  post op Chemo-XRT
• High Risk two or more positive lymph nodes,
  extracapsular spread, microscopic involvement of
  margins
• Increased disease free survival, increased
  locoregional control
• Overall Survival not significantly significant
• Substantial increase of severe side effects.

33
Adjuvant Chemotherapy18

• Adding chemotherapy to post op XRT for high risk
  H N SCC leads to a significant increase in
  local control and disease specific survival
• The impact of post op Chemo-XRT is greatest in
  tumors with extracapsular spread and/or
  microscopically involved margins
• Other risk factors include perineural invasion,
  vascular invasion, stage III/IV disease, and or
  level IV-V lymph nodes from tumors in the oral
  cavity or oropharynx.
• No change in incidence of distant metastases

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The Present

• Drug therapies are replacing a lot of medicines
  as we used to know it
• -George W. Bush

36
The Present

• Recent advances in molecular biology, including
  the human genome project have allowed for the
  introduction of targeted therapies for cancer.

37
Trastuzumab (Herceptin)19

• The type one receptor tyrosine kinases (ErbB
  receptors)
• Composed of an extracellular ligand binding
  domain,a transmembrane segment and an
  intracellular protein tyrosine kinase domain.
• Tyrosine Kinase receptor, that when activated,
  stimulates many intracellular signaling pathways,
  mainly mitogen activated protein kinase (MAPK)
  and the phosphatidylinositol 3 kinase (PI3K)-Akt
  pathway.
• Through these pathways the EGF receptor
  sitmulates cell growth, division,
  differentiation, migration, adhesion and
  angiogenic activity
• HER2 (erbB2) overexpressed in 20-25 of invasive
  breast cancer, and is associated with an
  increased risk of chemotherapy resistance,
  metastases, relapse and death in these patients.

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http//www.biooncology.com/bioonc/index.m
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Trastuzumab (Herceptin)20

• Trastuzumab- A recombinant humanized anti-erbB2
  monoclonal antibody which binds to the
  extracellular domain of the receptor and blocks
  intracellular signalling.
• Approved by FDA in 1998
• Blocks dimerization of the receptor and therefore
  intracellular phosphorylation.
• Anti-Body Mediated Cytotoxicity

41
Trastuzumab (Herceptin)

• Several International RCT of Trastuzumab with
  total enrollment gt13,000 patients were initiated
  in 2000-2001, and initial results became
  available in 200520
• Significantly Lower (46) risk of metastases,
  longer disease free survival and a trend towards
  longer overall survival
• Low incidence of adverse effects- in particular
  none of the toxic effects typically produced by
  chemotherapy nausea, vomiting, hair loss or
  myelosupression
• Cardiac Dysfunction When used with an
  anthracycline erbB-2 has an anti apoptotic role
  in normal myocytes, interruption of which leads
  to increased stress related cardiac damage

42
Imatinib (Gleevec)20

• ABL1 Protoncogene A tyrosine kinase found in
  both the nucleus and the cytoplasm that when
  activated, interacts with a number of signal
  transduction pathways including Ras, MAP, STAT,
  PI3K and Myc involved I gene transcription,
  apoptosis, cytoskeletal organization
• BCR-ABL Results from a reciprocal translocation
  between chromosomes 9 and 22
• This gene re-arrangement is present in nearly
  100 of cases of CML
• The gene product is found exclusively in the
  cytoplasm, and is constitutively active leading
  to a proliferative advantage and decreased
  apoptosis in affected cells

43
Imatinib (Gleevec)

• Imatinib Orally bioavailable inhibitor of the
  ABL protein
• Approved by FDA in May 2001
• Also blocks other kinases including PDGF, and
  c-Kit

44
Imatinib (Gleevec)

• Prior to Imatinib, CML typically followed an
  inexorable course that resulted in the death of
  the patient
• Only allogenic hematopoietic stem cell transplant
  has been shown conclusively to provide long term
  disease eradication
• Chronic Phase-gt Intermediate Phase -gt Blast Phase
• Traditional Chemotherapy with cytarabine and
  alpha-interferon was associated with significant
  toxicity and 5 year survival of less than 60

45
Imatinib (Gleevec)

• Phase 2 studies of IM in patients with
  accelerated phase CML showed hematologic response
  in 82 of patients. Complete in 17
• Large randomized trial of IM vs. IFN Alpha in
  patients with newly diagnosed chronic phase CML,
  showed a major response in 87 of patients as
  compared to 35 and an 95 freedom from
  progression at 30 months.
• Minimal side effects most common being myalgias
  and diarrhea

46
Epidermal Growth Factor Receptor in Head and Neck
Cancer

• EGFR ErbB125
• EGFR mRNA is upregulated in 92 of HNSCC22
• EGFR levels increase in in advanced stage tumors
  and in poorly differentiated tumors.
• Increased EGFR correlates with poorer clinical
  outcome22

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Cetuximab (Erbitux)

• Recombinant monoclonal antibody which binds to
  the extracellular domain of the EGF receptor with
  high affinity
• Block activation of receptor tyrosine kinase by
  EGF or TGF Alpha
• Induces antibody-mediated homodimerization and
  destruction25

50
Cetuximab (Erbitux)

• ECOG trial (Burtness et al.) 2005 117 patients
  randomized to Cisplatin vs. Cisplatin/Cetuximab.24
  
• Objective response improved in combined arm (26
  vs. 10)
• However, Primary end point of Disease free
  survival did not meet statistical significance
  (4.2 vs. 2.7 months)
• Cutaneous toxicity correlates with efficacy
• Trigo et al. 2004 103 patients who had
  progressed on platinum containing regimens.24
• Overall response rate of 13 with 5 complete
  responses
• Harari et al. 2004 424 patients with LR
  advanced H N Cancer randomized to XRT vs. XRT
  Cetuximab24
• 3 year survival rate of 57 vs. 44
• Locoregional Control Rate of 56 vs. 48

51
Gefitinib, Erlotinib

• Low molecular weight tyrosine kinase inhibitors
  which compete with ATP binding to the
  intracellular portion of the EGFR, blocking
  phosphorylation, and therefore activation of
  downstream signalling proteins.
• Erlotinib approved in US for NSCLC
• Gefitinib approved in Japan22

52
Gefitinib, Erlotinib24

• More Studied in NSCLC Where patients refractory
  to conventional chemotherapy have had up to 18
  response rates
• Studies in H N Cancer
• Gefitinib- Phase II trial of 47 patients showed
  10.6 response rate. Second study at low dose
  was less effective. Cutaneous toxicity correlated
  with efficacy.
• Erlotinib Phase II trial of 115 patients showed
  a 4 partial response rate.

53
Gefitinib, Erlotinib

• Why dont EGFR antagonists work better?25
• G Protein coupled receptors
• Constitutively activated downstream pathways
• Increased levels of VEGF
• Activation of other ErbBs

54
The Future
55
Bevacizumab26 (Avastin)

• VEGF (Vascular Endothelial Growth Factor) one
  of the most potent promoters of angiogenesis, has
  been identified as a fundamental regulator of
  tumor neovascularization
• Overexpressed in HN Cancer
• Indicates a poor response to chemo-XRT
• High levels of VEGF induced by XRT
• Bevacizumab (Avastin) recombinant humanized
  monoclonal antibody which binds to and
  neutralizes VEGF
• Has been studied in more than 30 different
  clinical trials, in multiple types of cancer
• A phase II study in H N cancer in combination
  with Erlotinib has recently opened.

56
EpCAM30

• EpCAM Epithelial Cell adhesion and activating
  molecule
• Over-expressed in a large variety of
  adenocarcinoma and SCC.
• Protects tumor cells from self proteolysis, and
  displays proliferative signalling activity
• Overeexpression correlates with negative
  prognosis
• ProxiniumR anti-EpCAM antibody fused to a
  subunit of the bacterial Pseudomonas endotoxin
• After EpCAM binding and endocytosis, endotoxin is
  cleaved and inhibits protein synthesis leading to
  cell death.
• Phase I/II trial shows 88 tumor response and
  median survival of 301 days vs. 125 days.
• Phase II/III trial is in progress
• Novel EpCAM immunotoxin is in development which
  is selectively cleaved by tumor cells.

57
Gene Therapy27

• At the end of Jan 2005, there were a total of
  1020 approved gene therapy clinical trials in the
  world
• 66 were for the treatment of cancer
• Cancer Gene Therapy is the delivery of specific
  genetic sequences into cells or tissues to
  achieve a therapeutic effect against malignant
  tumors.
• H N cancer is an ideal model
• Loco Regional Disease amenable to intratumoral
  injection
• Often presents with advanced disease inamenable
  to current therapies

58
Gene Therapy

• P53
• Tumor Suppressor Gene known as The guardian of
  the Genome
• Activates DNA Repair proteins when DNA has
  sustained damage
• Holds the cell cycle at G1 Regulation pointon
  Damage Recognition
• Initiates Apoptosis if DNA damage appears
  irrepairable

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http//www.biovita.fi/suomi/terveyssivut/p53.html
60
Gene Therapy27

• Restoration of p53 function
• Clayman et al. 1998 treated 18 patients with
  relapsed HNC with intratumoral injections of a
  replication deficient adenoviral vector
  expressing wild type p53
• One pathologic complete response, two partial
  responses, and 6 patients with disease
  stabilization
• Gendicine Recombinant human serotype 5
  adenovirus containing a human wild type p53
  expression cassette28
• Approved for use in H N cancer in China
• Phase III trial of 135 patients with late HN Ca
  (85NPC) randomized to Gendicine XRT vs. XRT
• 93 response vs. 79 however 64 Complete
  Response vs. 17
• Multicenter randomized Phase IV trial is in
  progress

61
Gene Therapy

• Onyx 015
• Replication competent viral vector containing a
  deletion in the E1B 55KD gene which is
  responsible for binding and inactivating p53
• Virus replicates preferentially in in p53
  deficient tumor cells and leads to cell death
• Phase II trial of intratumoral ONYX-015 in 36
  patients with relapsed HNC, there were 4 partial
  responses and 12 patients with stable disease
• More dramatic results in combination cisplatin

62
Immunotherapy

• Based on 2 Principles
• Immune system should recognize and destroy
  abnormal cells.
• Tumor Cells are poorly immunogenic, and strongly
  immunosupressive
• PGE2 produced by tumors inhibits lymphocyte
  proliferation
• Cytokines produced by tumors inhibit lymphocyte
  function
• Tumors down regulate antigen presenting molecules

63
Immunotherapy

• Interleukin 2 Produced by the body during an
  immune response, binds to the IL-2 receptor,
  stimulating the growth, differentiation, and
  survival of cytotoxic T cells
• Systemic injection associated with severe side
  effects
• Local injection into tumor short half life
  requires frequent injections.
• IRX-2 human cytokine mixture injected
  perilymphatically near tumor. Currently in
  clinical trials

64
Immunotherapy29

• Non-Specific Active Immunomodulation
• BCG vaccine
• Used to induce active, non specific stimulation
  of the immune system
• Reports of increased tumor free survival which
  could not be substantiated
• Trials with other vaccines (strep pyogenes,
  trypanosoma cruzi, levamisole) show no benefits
  in long term survival

65
Immunotherapy

• Specific Active Immunization
• P53 Mutated in gt80 of SCCHN which leads to a
  buildup of non functional p53 in cells.
• Since most mutations involve only one amino acid,
  Cytotoxic T cells which recognize WT p53 should
  also attack cells which express mutated p53
• In truth, patients who express mutated p53 are
  resistant

66
Immunotherapy

• HPV Vaccines
• Estimated that 25 of HNSCC are HPV associated31
• Tend to arise in younger patients
• Lingual and palatine tonsils
• Occur predominantly in non smoker/drinker
• Associated with a more favorable prognosis
• HPV viral oncogenes E6 and E7 are consistantly
  expressed in HPV associated cancers
• Thought to integrate into the host DNA, and when
  expressed, bypass the regulation of cell
  proliferation
• Both protein and DNA vaccines targeting HPV DNA
  are currently in phase I and phase II trials

67
Special Thanks To

• Jason Newman M.D.
• Duane Sewell M.D.

68
References

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