070125 chemotherapy for hn scc2

Chemotherapy For H&N SCC

Deepak passi

.

40,000 New cases of SCCHN each year in 2/3 Present with locally advanced lesions (T3

or T4)– 5 year survival <30%

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

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.

Methotrexate

Methotrexate

Toxicities:– Myelosupression, mucocitis, alopecia, N/V and

Diarrhea Most common– Renal Toxicity in Higher Doses

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.

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.

5-FU

Side Effects– MUCOCITIS– Other side effects include bone marrow supression,

N/V, alopecia and anorexia

Cisplatin

Cisdiamminedichlorplatinum (CDDP) Approved by USDA in 1978. Binds to Guanine on DNA, forming inter and

intra-strand crosslinks, inhibiting DNA synthesis.

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

Carboplatin

Mechanism is similar to that of Cisplatin Less Effective Lower Toxicity

Multi Agent Chemotherapy

In Mid 1980’s 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.

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

The Taxanes

Paclitaxel (Taxol) and Docetaxel (Taxotere) Isolated in 1960’s from the bark of the pacific

Yew tree (Taxus brevifolia) and introduced in 1990’s

Binds to the B subunit of tubulin, and stabilizes microtubules, interrupting mitosis and leading to cell death.

The Taxanes

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

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

Chemotherapy for Curable Disease

Induction or Neoadjuvant Chemotherapy Concomitant Chemotherapy Post Treatment or Adjuvant Chemotherapy

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


Meta-Analysis of Chemotherapy on Head and Neck Cancer (Pignon et al.) 20005

– Meta-analysis of >10,000 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

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


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


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.


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


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

Adjuvant Chemotherapy


Post operative XRT has been the standard approach for high risk H&N SCC since first pioneered by Fletcher and Evers in the early 1970’s.

However, the few randomized studies of post operative chemotherapy in the 1990’s yielded disappointing results.


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


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.

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

The Present

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

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.

http://www.biooncology.com/bioonc/index.m

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

Trastuzumab (Herceptin)

Several International RCT of Trastuzumab with total enrollment >13,000 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

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

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

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-> Intermediate Phase -> Blast Phase– Traditional Chemotherapy with cytarabine and alpha-interferon

was associated with significant toxicity and 5 year survival of less than 60%

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

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

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

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%

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

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.

Gefitinib, Erlotinib

Why don’t EGFR antagonists work better?25

– G Protein coupled receptors– Constitutively activated downstream pathways– Increased levels of VEGF– Activation of other ErbBs

The Future

Otorhinolaryngology: Head and Neck Surgery at PENN Excellence in Patient Care, Education and Research since 1870

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 H&N 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.

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.

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

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

http://www.biovita.fi/suomi/terveyssivut/p53.html

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 (85%NPC)

randomized to Gendicine + XRT vs. XRT– 93% response vs. 79% however 64% Complete Response vs. 17%– Multicenter randomized Phase IV trial is in progress

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

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

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

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

Immunotherapy

Specific Active Immunization– P53 – Mutated in >80% 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

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

070125 chemotherapy for hn scc2

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