Hypofractionated Reduced-Volume Chemoradiation for T1/2N0-2 SCC Head and Neck

Head and neck squamous cell carcinomas (HNSCC) are frequently occurring tumors with more than
500,000 new cases worldwide and 45,000 in the USA yearly . Most patients present with
local-regionally advanced diseases. Chemotherapy given concurrently with radiation is an
integrated treatment component in the management of these patients. Concurrent chemoradiation
can be given in unresectable diseases, in organ preservation to avoid surgery and preserve
functions, and in high risk patients after surgery . Randomized clinical trials and
meta-analyses have shown that concurrent chemoradiation are superior to radiation alone in
these settings.

One way of reducing overall treatment time and toxicity is to reduce the number of fractions
by increasing the daily radiotherapy dose. The consequence of increased daily dose is both an
increase in acute side effects as well as an increase in late toxicity. A widely accepted
model of these radiobiologic effects over the range of typical 2-4 Gy daily fractions is the
alpha-beta model that distinguishes acute responses and late responses based on a
linear-quadratic fitting of extrapolated clonogenic survival curves. A time factor can be
incorporated to account for the effect of repopulation. Equivalent biologically effective
dose schedules using a reduced number of fractions may be calculated for any conventionally
fractionated course. Because 70Gy/35/6 weeks with chemoradiation has been demonstrated to be
tolerable, and because 66Gy/30/6 weeks has been shown with IMRT to produce 90% control for
T1/2 oropharyngeal primary tumors, we will take the biological equivalent of 66Gy/33
fractions over six weeks as the biologic equivalent standard we wish to maintain in
hypofractionated courses of radiation. Because 54Gy/30 over six weeks is a well-known
elective radiation dose schedule producing 95% control of occult nodal disease, we will take
this as the biologically equivalent standard we wish to maintain in our hypofractionated
schedules.

Inclusion Criteria:

1. T1/2N0-2M0 SCC of the oropharynx, hypopharynx or larynx

2. Age ≥ 18 years.

3. Performance status ECOG 0-1

4. Adequate organ and marrow function as determined by medical oncology evaluation.

5. Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 90 days following completion of therapy.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.

6. A female of child-bearing potential is any woman (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the following
criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy; or

- Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has
had menses at any time in the preceding 12 consecutive months).

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

8. Creatinine clearance (CC) ≥ 50 ml/min within 4 weeks prior to registration
determined by 24-hour collection or estimated by Cockcroft-Gault formula: CCr male =
[(140 - age) x (wt in kg)]/[(Serum Cr mg/dl) x (72)] (CCr female = 0.85 x (CrCl
male)).

9. History/physical examination within 4 weeks prior to registration, including
assessment of weight and weight loss in past 6 months.

10. Medical oncology examination to evaluate medical contraindications prior to start
chemotherapy 11 Dental evaluation with management prior to start of radiation 12
Nutrition evaluation with consideration of percutaneous endoscopic gastrostomy (PEG)
tube placement 13 No distant metastasis by PET/CT

Exclusion Criteria:

1. T3/4 or N3

2. T1N0 disease

3. Metastatic disease

4. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years

5. Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields

6. Primary site of tumor of oral cavity, nasopharynx, sinuses, or salivary glands

7. Neck adenopathy that involves the overlying skin.

8. Initial surgical treatment including tonsillectomy or neck dissection, but excluding
diagnostic biopsy of the primary site or nodal sampling of neck disease

9. Pre-existing grade > 2 peripheral sensory neuropathy

10. Subjects may not be receiving any other investigational agents.

11. Uncontrolled intercurrent illness including, but not limited to, 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.

12. Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.