A Pilot Study of Induction Chemotherapy Followed by Surgery for Locally Advanced Resectable Head and Neck Cancer

An important observation of the induction triple chemotherapy regimen know as TPF is that
there was an unprecedented high proportion of patients treated who had a complete response
of their disease upon the completion of the induction phase. In a recent study by Haddad, et
al., a biopsy was performed in all patients following induction chemotherapy and before
starting concomitant chemoradiotherapy. Patients with an incomplete response to
chemoradiotherapy or who had N3 disease had a neck dissection 6 to 12 weeks after
chemoradiotherapy. Twenty-nine neck dissections were performed after chemoradiotherapy. The
neck dissection result was pathologically positive in 7 (24%) patients (all alive with no
evidence of disease) and negative in 22 (76%) patients (21 alive with no evidence of
disease). Post-TPF, primary site biopsy result was negative in 64 patients (89%) and
positive in 8 patients (11%). While the protocol required all patients to subsequently
receive concomitant chemoradiation regardless of disease response to the induction component
of the regimen, it is reasonable to question whether the complete responder subset really
needed to undergo the same intensive chemoradiation treatment compared to the partial
responders. Thus, a less intense therapy may be sufficient. The long term goal of this
protocol is to alter the model of highly effective cancer therapy from what is maximally
tolerated by the patient to what is minimally necessary for a cure.

One treatment strategy for patients with advanced head and neck cancer who prove to be
highly sensitive to chemotherapy is to combine the modalities of polychemotherapy and
conservation surgery with the goal of avoiding radiation therapy. For those patients whose
primary disease is classified as T2-3 (resectable), and who have a complete response
following induction therapy, it is feasible to perform an organ preservation tumor
nidusectomy at the primary site to verify that the clinical complete response is truly
pathological complete response. Similarly, the clinical complete response observed for the
associated nodal disease, can be verified pathologically by performing a selective neck
dissection without causing significant morbidity. Both tumor nidusectomy and selective neck
dissection has been shown to be an effective adjuvant in this setting. Building on these
observations, the novel protocol outlined in this proposal has the potential to spare the
use of radiation therapy for selective patients who have a complete response to induction
chemotherapy and thereby improve their well being without compromising survival.

Inclusion Criteria:

1. Ability to understand and the willingness to sign a written informed consent
document.

2. Histologically confirmed Stage III-IV (T1, T2, T3) (N0-N2) squamous cell carcinoma of
the oropharynx staged according to AJCC guidelines.

3. The subject must be considered surgically resectable via a transoral approach at the
time of presentation.

4. Age >18 years

5. Life expectancy >/= 5 years

6. ECOG performance status <2

7. Subject must have measurable disease, at least one lesion accurately measured in at
least one dimension as >10 mm with CT scan.

8. Hematologic Absolute neutrophil count > 1,000/mm3, Hemoglobin > 8.0 g/dl Platelet
count > 100,000/mm3 Leukocytes >3,000/mcL

9. Hepatic Total Bilirubin ≤ ULN; AST and ALT and Alkaline Phosphatase within the
eligible range

10. Renal - creatinine within normal institutional limits or >60 mL/min/1.73 m2
creatinine > institutional normal

11. Women of childbearing potential with negative pregnancy test.

12. Men and women of childbearing age willing to use effective contraception

Exclusion Criteria:

1. N3 nodal disease according to AJCC guidelines

2. Retropharyngeal nodal involvement

3. Trismus

4. Second primary head and neck tumor unless it is/was a basal or squamous cell skin
cancer

5. Prior surgery, chemotherapy, biologic or radiotherapy for a head or neck malignancy

6. Concurrent investigational agent or intervention (within 90 days of screening visit)

7. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to docetaxol, cisplatin, 5- fluorouracil, or carboplatin.

8. History of severe hypersensitivity reaction to drugs formulated with polysorbate 80

9. Breastfeeding women

10. Pre-existing peripheral neuropathy grade > 3

11. Evidence of distant metastatic disease

12. Unknown primary site

13. Prior or concurrent malignancies (excluding adequately treated basal or squamous cell
skin cancer, in situ cervical cancer, stage I or II cancer from which the subject has
been in complete remission for at least 12 months (excluding head and neck), any
cancer from which the subject has been cancer free for 5 years)

14. History of allergies to any of the pre-medications.

15. Investigator consideration based upon screening interview and/or procedures

16. Evidence of bone invasion/destruction

17. Uncontrolled intercurrent illness including ongoing or active infection, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements

18. Pregnant women

19. History of HIV, hepatitis B, hepatitis C, or delta antigen

20. Known allergy to India Ink or methylene blue