2007 HN Docetaxel

GBMC Head and Neck Conference
The Role of Docetaxel in

the Treatment of Head
and Neck Cancer
Simon Best
December 7, 2007
Needs assessment:
Providers who participate in the care of head and neck cancer
patients should be aware of the newest evidence for novel
chemotherapeutic agents. Recent multi-center randomized-
controlled trials provide support for the use of Docetaxel in
head and neck cancer.
Objectives:
1) Provide an overview of the mechanism and use of taxane
drugs.
2) Review recent clinical evidence supporting the use of
Docetaxel
Financial Disclosure:
None
Case Presentation
CC: Worsening dyspnea
HPI: 63 y/o retired office manager with subacute to acute worsening
dyspnea. Evaluation by ENT who identified a transglottic tumor,
development of acute SOB required admission to hospital and emergent
trach.
PET/CT – Mass involving R larynx, extending through cricoid cartilage
with involvement of soft tissue anterior, 8 mm jugular node on R; no
distant metastases identified
PMH: COPD, depression, breast cancer, macular degeneration, HTN
PSH: R mastectomy + neoadjuvent / adjuvent chemotherapy
SH: 80 pack-year smoking hx, rare ETOH, no other drugs of abuse
Medications: Paxil, Spiriva, Albuterol, Protonix
Case Presentation Cont.
Surgical Treatment:
12/06 – Emergent tracheotomy, PEG
1/07 – Total laryngectomy, B ND 2A-4, TEP,
paratracheal dissection
Pathology: Negative margins, + perineural invasion.
4/20 nodes on R, 0/18 nodes on L
Medical Treatment:
Recommended chemoradiation but pt declined
Case Presentation cont.
7/07: Presented to head & neck cancer center with
small fistula, bleeding
8/07: Central neck mass, biopsy proven SCC
CT scan: 4x5x4 cm recurrence in hypopharynx, extending to
BOT and oropharynx
PET: Multiple lung nodules suspicious for malignancy,
possible involvement of mandible
Medical Oncology consult
Due to personal hx of chemotherapy, metastatic disease pt
recommended for investigational plan utilizing cisplatin,
docetaxel, and panitumumab.
Panitumumab (Vectibix) – human monoclonal antibody to EGF
receptor. FDA approved for EGFR-expressing metastatic colon
cancer. IgG2 antibody, cetuximab is an IgG1 antibody.
Receiving – Cisplatin, Taxol, 5-FU
Taxol (paclitaxel)
1955: NCI sets up screening for anti-cancer
compounds
1960: NCI commisions USDA to collect 1000
biologic specimens per year
1962: Specimen collected from Pacific Yew tree
Taxus brevifolia
1964: Found to be cytotoxic, purified, published
1971: Chemical structure
Taxol cont.
1978: Activity in xenografts, leukemic mice
1979: Mechanism of action published in Nature
Binds to beta subunit of tubulin, hyperstabilizes microtubule
structure – causes arrest of ‘dynamic instability’, arrests
mitosis, causes apotosis
1982: Animal studies
1984: Phase I human studies – 60,000 tons of bark
USDA program shut down in 1981 – 114,000 plant; 16,000
animal compounds tested
1989: Published data from Phase II trial showed 30%
response rate in end stage ovarian cancer
Taxol cont.
1989: NCI announces open Cooperative
Research and Development Agreement with
drug company willing to commercially develop,
synthesize compound, and fund clinical studies
Proprietary access to data, all biologic specimens
BMS wins contract, files for patent application
(granted in 1992)
5 year exclusive marketing rights
2003 Congressional Accounting Report found that
NIH “failed to ensure value for money”
Taxol cont.
Until 1993, almost all compound produced was from
bark of Pacific Yew
40 ft tree, 200 years old produces 0.5 g of taxol
Pierre Potier (France): semi-synthetic process using
needles of Taxus baccata but with poor yield
Robert Holton (FSU): improved yield to 82% by 1992
– deal signed between BMS and FSU to patent this and
all future synthetic processes
Total synthetic synthesis in Dec, 1993
1995: BMS announces end of reliance on Pacific yew
FSU totals over $200 million in royalties from BMS
Docetaxel (Taxotere)
Marketed by Sanofi-Aventis
Semi-synthetic analogue of Taxol
From European yew tree
Developed in France following synthetic pathways
discovered by Pierre Potier
Identical mechanism of action, longer
microtubule chains
Resistance to paclitaxel does not imply resistance to
docetaxel
Docetaxel cont.
IV formulation – 100%
bioavailability
Liver metabolism
Hemotologic side effects
Neutropenia – 95%
Anemia – 90%
Febrile neutropenia – 11%
Thrombocytopenia – 8%
Death 1.7%
Incidence ~10% in
patients with elevated liver
enzymes
Chemotherapy Definitions
Induction / Neoadjuvant: Use of chemotherapy before
other treatment (surgery or radiotherapy)
Concomitant / Concurrent: Use of chemotherapy

simultaneously with other treatment
Adjuvant: Use of chemotherapy in postoperative setting
Palliative: Use of chemotherapy without curative intent

Chemotherapy and H+N cancer
60% of patients present with Stage III/IV disease
Chemotherapy and radiation the standard of care for

majority of locally advanced and unresectable disease
Hyperfractionated irradiation with or without concurrent chemotherapy
for locally advanced head and neck cancer. Brizel DM, N Engl J
Med. 1998 Jun 18;338(25):1798-804 [116 pts]
Large survival benefit for concurrent therapy compared to radiation
alone
Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the
Head and Neck. Bonner JA, N Engl J Med 2006 Feb 9;
354(6):567-78. [424 pts]
Addition of cetuximab improved locoregional control and mortality
Brizel
Radiation: Hyperfractionated irradiation
received 125 cGy twice daily, for a total of 7000
cGy
Chemotherapy
5 treatments of Cisplatin + Fluorouracil during
weeks 1-6
2 extra doses after completion of radiation
Induction Chemotherapy
What is the evidence for induction?
Domenge C. Br J Cancer 2000 [318 pts]

Neoadjuvant therapy with cisplatin + fluorouracil for 3 cycles followed by
local-regional control (surgery or radiation alone) [1986-1992]
Neoadjuvant improved survival regardless of method of local control
Paccagnella. J Natl Cancer Inst 1994 [237 pts]

Neoadjuvant therapy with cisplatin + fluorouracil followed by local-
regional control
For operable patients, the only benefit from neoadjuvant chemotherapy was a
significant reduction in the incidence of distant metastases. For inoperable
patients, neoadjuvant chemotherapy improved local control, decreased the
incidence of distant metastases, and improved the complete remission rate
and overall survival.
Taxanes and H+N Cancer
1994: Docetaxel used as single agent
chemotherapy in Phase II trial – response rate of
32% (9% complete)
1996: Docetaxel used as single agent
chemotherapy in Phase II trial – response rate of
42% (10% complete)
2000s: Multiple multidrug Phase II feasibility
trials
1st Article
Cisplatin, Fluorouracil, and Docetaxel in
Unresectable Head and Neck Cancer
EORTC 24971 / TAX 323 Study Group
Multi-center study involving 358 patients accrued between
1999 - 2002
Study Design:
PF or TPF cycles q3week x up to 4 treatments
Imaging of tumor cycles 2 and 4
Radiation (either conventional or hyperfractionated) within 4-7 weeks
after completion of chemo for 7 weeks
Neck dissection ‘considered for all patients before radiotherapy and 3
months after the completion of radiotherapy’
Key Findings
Table 1: Patient Demographics
Figure 1: Majority of patients finished chemotherapy (76% TPF,
66% PF)
Similar with respect to number of chemo cycles and duration
No difference in radiation treatments
Figure 2: 273 patients had disease progression or died
TPF resulted in 28% relative reduction in risk of disease progression or
death
TPF improved overall survival
Table 2: Higher response and complete response rate in TPF
group for both chemotherapy alone and after locoregional
control
Higher rate of surgery in TPF group (40 vs. 20 pts)
Table 3: Adverse Reactions
Higher neutropenia, leukopenia in TPF, most other adverse reactions
higher in PF
Discussion
Median 2.8 months extension in progression-
free survival, median overall survival improved
by 4.3 months
Survival shorter than in other Phase 3 trials
Hyperfractionated radiation not yet accepted as
standard at start of trial
2nd Article
Cisplatin and Fluorouracil Alone or with Docetaxel
in Head and Neck Cancer
TAX 324
Multi-center study involving 539 patients from 1999 to 2003
37 patients excluded because of computer error in randomization
Study Design:
PF or TPF cycles q3weeks for 3 cycles (slightly higher dose of F in
TPF group compared to previous study)
Chemoradiation began 3 to 8 weeks after completion of induction,
carboplatin + radiation to 70 Gy over 7 weeks
Surgery performed 6 to 12 weeks after chemoradiation for all initial
N2 and partial response, N3, or residual disease
Key Findings
Table 1: Patient demographics
TPF group had higher T4 after randomization
Table 2: Very high percentage finish initial chemotherapy,
dropout during chemoradiation
Figure 1: 234 pts died at study cutoff (47%)
TPF resulted in 30% reduction in risk of death
Table 3: TPF associated with trend toward improved survival in
all subgroups
Median survival 71 vs. 30 months
TPF with less locoregional failure; same amount of distant metastases and
second primaries
Overall response rate after induction and complete response rate not
statistically significant
Table 4:
Neutropenia, febrile neutropenia, neutropenic infections higher in TPF
Despite this, fewer treatment delays in TPF
Comparison
Chemo:
Radiation:
Patients:
Ages:
Stages:
Extension of Progression-free survival:
Extension of Overall survival:
The Big Question
Does induction chemotherapy plus radiation
give equal results to chemoradiation?
Does induction chemotherapy function as a
complement to chemoradiation?
Only one Phase 3 trial to compare induction
chemo, chemoradiotherapy and radiotherapy
alone
PF induction equivalent to chemoradiation
Both superior to radiation alone

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GBMC Head and Neck Conference

The Role of Docetaxel in

Concomitant / Concurrent: Use of chemotherapy

Adjuvant: Use of chemotherapy in postoperative setting

Palliative: Use of chemotherapy without curative intent

Chemotherapy and radiation the standard of care for

Domenge C. Br J Cancer 2000 [318 pts]

Paccagnella. J Natl Cancer Inst 1994 [237 pts]

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