Clinical trial NCT01111942: A Pilot Study of Induction Chemotherapy Followed by Surgery for Locally Advanced Resectable Head and Neck Cancer
Official title: A Pilot Study of Induction Chemotherapy Followed by Surgery for Locally Advanced Resectable Head and Neck Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Head and Neck Cancer
Keywords: head and neck cancer
chemotherapy
radiation
Lead sponsor: Southern Illinois University
Sponsor class: OTHER
First posted: 2010-04-28
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: This is a non-randomized open-label investigator initiated pilot study comparing follow-up therapy of advanced head and neck cancer subjects initially treated with triple induction chemotherapy. Subjects will receive surgical treatment or combined chemoradiation therapy based on the subject's apparent clinical response. Spared use of radiation therapy for selective patients who have a complete response to induction chemotherapy could improve well being of this patient population without compromising survival.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Rate of pathologic complete response
timeFrame: 42 months
Secondary outcomes:
measure: 2 year overall survival
timeFrame: 42 months
measure: Clinical complete response
timeFrame: 42 months
measure: 2 year disease-free survival
timeFrame: 42 months
measure: Quality of life
timeFrame: 42 months
measure: Incidence of HPV and EGFR positivity
timeFrame: 42 months
measure: K-ras mutational analysis
timeFrame: 42 months
Other outcomes:
Locations:
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
Study officials:
affiliation: Southern Illinois University School of Medicine
name: K. T. Robbins, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Southern Illinois University School of Medicine
name: Krishna Rao, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Robbins KT, Howell SB, Williams JS. Intra-arterial chemotherapy for head and neck cancer: is there a verdict? Cancer. 2010 May 1;116(9):2068-70. doi: 10.1002/cncr.24930. No abstract available.
citation: Malone J, Robbins KT. Neck dissection after chemoradiation for carcinoma of the upper aerodigestive tract: indications and complications. Curr Opin Otolaryngol Head Neck Surg. 2010 Apr;18(2):89-94. doi: 10.1097/MOO.0b013e32833693e7.
citation: Malone JP, Gerberi MA, Vasireddy S, Hughes LF, Rao K, Shevlin B, Kuhn M, Collette D, Tennenhouse J, Robbins KT. Early prediction of response to chemoradiotherapy for head and neck cancer: reliability of restaging with combined positron emission tomography and computed tomography. Arch Otolaryngol Head Neck Surg. 2009 Nov;135(11):1119-25. doi: 10.1001/archoto.2009.152.
citation: Rogers LQ, Rao K, Malone J, Kandula P, Ronen O, Markwell SJ, Courneya KS, Robbins KT. Factors associated with quality of life in outpatients with head and neck cancer 6 months after diagnosis. Head Neck. 2009 Sep;31(9):1207-14. doi: 10.1002/hed.21084.
citation: Robbins KT, Homma A. Intra-arterial chemotherapy for head and neck cancer: experiences from three continents. Surg Oncol Clin N Am. 2008 Oct;17(4):919-33, xi. doi: 10.1016/j.soc.2008.04.015.