phase ii trial of post-operative concurrent radiation and cetuximab for locally advanced cutaneous squamous cell carcinoma of the head and ne

Phase II Trial of Post-operative Concurrent Radiation and Cetuximab
for Locally Advanced Cutaneous Squamous Cell Carcinoma of the Head and
Neck
PI:
Brad Huth MD
Assistant Professor
Department of Radiation Oncology
Co-PIs:
William Barrett MD
Professor
Department of Radiation Oncology
John Morris MD
Professor
Department of Internal Medicine
Division of Hematology Oncology
Yash Patil MD
Associate Professor
Department of Otolaryngology
Kevin Redmond MD
Associate Professor
Department of Radiation Oncology
Changchun Xie, PhD
Assistant Professor
Department of Epidemiology and Biostatistics
Keith Wilson MD
Associate Professor
Department of Otolaryngology
Michelle Mierzwa MD
Assistant Professor
Department of Radiation Oncology
University of Michigan
Keith Casper MD
Assistant Professor
Department of Otolaryngology
University of Michigan
Avi Eisbruch MD
Professor
Department of Radiation Oncology
University of Michigan
Francis Worden MD
Associate Professor
University of Michigan
Carol Bradford MD
Professor and Chair
Department of Otolaryngology
University of Michigan
Mark Prince MD
Professor
Department of Otolaryngology
University of Michigan
Matthew Spector MD
Assistant Professor
Department of Otolaryngology
University of Michigan
Andrew Shuman MD
Assistant Professor
Department of Otolaryngology
University of Michigan
Kelly Malloy MD
Assistant Professor
Department of Otolaryngology
University of Michigan
Chaz Stucken MD
Assistant Professor
Department of Otolaryngology
University of Michigan
Roadmap
Eligibility: cutaneous squamous cell carcinoma with invasion of any
skeletal muscle, cartilage, bone or lymph nodes of the head and neck
after resection

Enrollment

`
Day 8 - 55:
Weekly Cetuximab 250mg/m2 (x7 doses)
+
RT 60-66 Gy
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Table of Contents
Protocol Roadmap 2
1. Background 5
1.1 Locally advanced cutaneous cancer 5
1.2 Study Design 5
1.3 Epidermal Growth Factor Receptor 5
1.4 Cetuximab 6
1.5 Safety of Cetuximab in SCCHN Clinical Studies 7
1.6 Translational Science 10
1.7 Quality of Life and Functional Assessments 10
2. Objectives 12
2.1 Primary Objectives 12
2.2 Secondary Objectives 12
2.3 Tertiary Objectives 12
3.0 Patient Selection 12
3.1 Conditions for Patient Eligibility 12
3.2 Conditions for Patient Ineligibility 13
4. Pretreatment Evaluations/Management 15
4.1 Required Evaluations/Management 15
4.2 Highly Recommended Evaluations/Management 15
5.0 Registration Procedures 15
6. Radiation Therapy 15
6.1 Dose Specifications 15
6.2 Technical Factors 15
6.3 Localization, Simulation, and Immobilization 16
6.4 Target and Normal Tissue Volume Definitions 16
6.5 Treatment Planning and Delivery 18
6.6 Compliance Criteria 19
6.7 RT Quality Assurance Reviews 19
6.8 Radiation Therapy Adverse Events 19
7. Drug Therapy 20
7.1 Cetuximab Initial Dose 21
7.2 Cetuximab Subsequent Doses 21
7.3 Cetuximab Dose Modifications 26
7.4 Adverse Events 28
8. Tissue/Specimen Submission 29
9. Patient Assessments 29
9.1 Study Parameters 29
9.2 Evaluation during Radiotherapy 29
9.3 Evaluation in Follow-up 29
9.4 Outcomes Criteria 30
9.5 Quality of Life and Functional Assessments 30
9.6 Criteria for Discontinuation of Protocol Treatment 31
10. Statistical Considerations 32
11. Data and Safety Monitoring 33
1.1 Locally Advanced Cutaneous Cancer
Cutaneous squamous cell carcinomas are very common malignant neoplasms
in the United States, frequently associated with sun exposure and fair
complexions. Other risk factors include advanced age and acquired
immunosuppression after solid organ transplantation or treatment for
leukemia/lymphoma.
Squamous cell carcinomas of the skin are considered aggressive
non-melanoma skin cancers. Cutaneous squamous cell carcinomas of the
head and neck (CSCCHN) occur commonly, and this is reflected in the
AJCC seventh edition 2010 staging, which created new staging for
non-melanoma skin cancer staging that correlates with the head and
neck mucosal staging1.
Within CSCCHN, poor prognosis has been associated with involvement of
the parotid gland, advancing cervical nodal metastases,
immunosuppression, and bony involvement. Overall survival at 2 years
in retrospective studies2-3, was 70-80% for N1 parotid and/or neck
involvement, whereas it was 25-50% for N2-3 patients. It has been
reported that immunocompromised patients have a 7.2 fold increased
risk of local recurrence and a 5.3 fold increased risk of any
recurrence after treatment for CSCCHN. Mortality is also increased
with skin cancer; skin cancer was the fourth most common cause of
death in a reported renal transplant cohort 4. Additionally, single
institution series have reported that histopathology of CSCC in
immunocompromised patients is more aggressive, with tumor size being
less important 5. The 2010 AJCC staging manual documents increased
local failure rates for tumors with invasion of skeletal muscle or
cartilage.
CSCCHN is most commonly managed with primary surgery, although very
locally advanced lesions can be palliated with primary radiotherapy.
After radical resection, indications for post-operative radiotherapy
include positive surgical margins, perineural invasion, positive lymph
nodes, invasion of bone or cartilage and extensive skeletal muscle
infiltration. Despite surgery and post-operative radiotherapy,
approximately 25% patients will experience loco-regional failure, 25%
will develop distant metastases and the 2 year overall survival is
several large series is reported to be 40-55%6 7 8. In our experience
at the University of Cincinnati, loco-regional control with surgery
and post-operative radiotherapy alone has been 68% (unpublished).
While these numbers could certainly be improved upon, there have been
no prospective trials to date looking at the addition of chemotherapy
or targeted therapies to radiotherapy in this setting.
1.2 Study Design
Postoperative RT alone is the current standard of care for patients
with locally advanced cutaneous malignancies of the head and neck,
with suboptimal outcome. The goal of this trial is prospectively study
the addition of concurrent cetuximab to radiotherapy for locally
advanced CSCCHN in the post-operative setting for CSCCHN.
1.3 Epidermal Growth Factor Receptor (EGFR)
In mucosal SCCHN, a recent important area of advance has been the
study of epidermal growth factor receptor (EGFR). EGFR is expressed at
very high levels in the majority of human mucosal head and neck
squamous cell carcinoma (SCCHN). Furthermore, pre-clinical data
indicate that it is not merely a ‘bystander’ but is intimately
associated with the malignant phenotype of SCCHN. EGFR activation in
response to a ligand (e.g., EGF or TGF-alpha) results in
phosphorylation of its intracytoplasmic tyrosine kinase domain,
leading to a cascade of signal transduction within the cell. This
ultimately leads to DNA synthesis, cell proliferation, anti-apoptosis,
and transcription of growth factors such as pro-angiogenic molecules.
Blockade of this pathway is an effective anti-neoplastic strategy;
furthermore, EGFR blockade appears to result in radiosensitization.
This hypothesis was proven in a randomized trial by Bonner, et al.
(2006)9. In that study, patients with locally advanced, non-operative
mucosal SCCHN were randomized to RT alone or RT with weekly cetuximab.
Local-regional control and survival were significantly improved with
cetuximab. 2-year locoregional control was increased significantly
with cetuximab by 9% (from 41 to 50%), and this translated into an
overall survival advantage at 5 years. 5-year overall survival was 45%
for RT/cetuximab, compared with 36% for RT alone. Interestingly, the
development of > grade 2 rash associated with cetuximab was associated
with significantly improved overall survival.
1.4 Cetuximab
Cetuximab is a humanized monoclonal antibody against the EGFR
receptor. In the Bonner study of cetuximab and radiotherapy for
locally advanced non-operative mucosal SCCHN described above,
cetuximab appeared to have little toxicity when given concurrently
with radiotherapy for mucosal SCCHN and 93% of patients received the
prescribed cetuximab dose [Bonner 2006]. Furthermore, the Bonner study
showed no evidence that cetuximab increased the rate of ≥ Grade 3
mucositis or dysphagia, no evidence of an increased rate of late
effects, and no evidence of a worsening of QOL relative to RT alone.
The Bonner study is not the only data in support of cetuximab as a
valuable treatment against mucosal head and neck cancer. Cetuximab is
currently under investigation in the post-operative setting for
mucosal intermediate risk SCCHN in RTOG 0920. In platinum-refractory
recurrent/metastatic mucosal SCCHN, single agent cetuximab has a
response rate of approximately 11%10, providing further clinical
evidence that it is working via a pathway (or pathways) distinct from
DNA damaging agents such as platins or RT. In first-line therapy for
recurrent/metastatic SCCHN, the addition of cetuximab to 5-
FU/platinum significantly improved overall survival 11.
In locally advanced unresectable CSCCHN, cetuximab has been
investigated as a single agent, demonstrating 69% disease control rate
at 6 weeks by RECIST criteria12. Seventy-eight percent of patients
developed grade 2 acneiform rash, which was associated with prolonged
disease free survival. To date, cetuximab has not been investigated
concurrently with radiotherapy in the setting of cutaneous malignancy.
Based upon the data described above, we propose testing concurrent
cetuximab with postoperative RT for those patients who have a high
risk of recurrence as results with radiotherapy alone are suboptimal.
We will compare the results of the current study with historical
results using the current standard of care for these patients (RT
alone).
1.5 Safety of Cetuximab in SCCHN Clinical Studies
Cetuximab has been evaluated in 208 patients with locally or
regionally advanced SCCHN who received cetuximab in combination with
radiation and as monotherapy in 103 patients with recurrent or
metastatic SCCHN. Of the 103 patients receiving cetuximab monotherapy,
53 continued to a second phase with the combination of cetuximab plus
chemotherapy. Patients receiving cetuximab plus radiation therapy
received a median of 8 doses (range 1-11 infusions). The population
had a median age of 56; 81% were male and 84% Caucasian. Patients
receiving cetuximab monotherapy, received a median of 11 doses (range
1-45 infusions). The population had a median age of 57; 82% were male
and 100% Caucasian. The most serious adverse reactions associated with
cetuximab in combination with radiation therapy in patients with head
and neck cancer were: infusion reaction (3%); cardiopulmonary arrest
(2%); dermatologic toxicity (2.5%); mucositis (6%); radiation
dermatitis (3%);confusion (2%);diarrhea (2%).
Fourteen (7%) patients receiving cetuximab plus radiation therapy and
5 (5%) patients receiving cetuximab monotherapy, discontinued
treatment primarily because of adverse events. The most common adverse
events seen in 208 patients receiving cetuximab in combination with
radiation therapy were acneiform rash (87%), mucositis (86%),
radiation dermatitis (86%), weight loss (84%), xerostomia (72%),
dysphagia (65%), asthenia (56%), nausea (49%), constipation (35%), and
vomiting (29%).
The most common adverse events seen in 103 patients receiving
cetuximab monotherapy were acneiform rash (76%), asthenia (45%), pain
(28%), fever (27%), and weight loss (27%).
The data in the table below are based on the experience of 208
patients with locoregionally advanced SCCHN treated with cetuximab
plus radiation therapy compared to 212 patients treated with radiation
therapy alone (Cetuximab [Erbitux™] package insert, 2006).


Late Radiation Toxicity
The overall incidence of late radiation toxicities (any grade) was
higher in cetuximab in combination with radiation therapy compared
with radiation therapy alone. The following sites were affected:
salivary glands (65% versus 56%), larynx (52% versus 36%),
subcutaneous tissue (49% versus 45%), mucous membrane (48% versus
39%), esophagus (44% versus 35%), skin (42% versus 33%), brain (11%
versus 9%), lung (11% versus 8%), spinal cord (4% versus 3%), and bone
(4% versus 5%). The incidence of Grade 3 or 4 late radiation
toxicities were generally similar between the radiation therapy alone
and the cetuximab plus radiation treatment groups.
Clinically Relevant Adverse Events Related to Cetuximab
Pooled adverse event data are available for 2,127 patients treated
with cetuximab alone or in combination with chemotherapy and/or
radiation therapy (21 ImClone studies, 9 Merck KgaA, 2 BMS, and 1 ECOG
study). A total of 90.3% of the patients reported adverse events
(AEs). Approximately two-thirds (64.8%) of patients reported at least
one Grade 3 or 4 event. Cetuximab-related AEs were observed in 1,817
patients (85.4%). The most common composite groupings of adverse
events deemed related to cetuximab as reported by investigators in all
cetuximab trials (N = 1,817) include acneiform rash (76.2%), acne-like
rash (72.4 %), fatigue/malaise/lethargy (30.1%), nausea/vomiting
(24%), mucositis/stomatitis (17.5 %), infusion-related symptoms
(15.6%), diarrhea (15.4 %), and hypersensitivity reaction (5.3%).
Acne-Like Rash
In clinical studies of cetuximab, dermatologic toxicities, including
acneiform rash, skin drying and fissuring, and inflammatory and
infectious sequelae (e.g., blepharitis, cheilitis, cellulitis, cyst)
were reported. In patients with advanced colorectal cancer, acneiform
rash was reported in 89% (686/774) of all treated patients, and was
severe (grade 3 or 4) in 11% (84/774) of these patients. Subsequent to
the development of severe dermatologic toxicities, complications
including S. aureus sepsis and abscesses requiring incision and
drainage were reported. Non-suppurative acneiform rash described as
“acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or
“exfoliative dermatitis” was observed in patients receiving cetuximab
plus irinotecan or cetuximab monotherapy. One or more of the
dermatological adverse events were reported in 88% (14% grade 3) of
patients receiving cetuximab plus irinotecan and in 90% (8% grade 3)
of patients receiving cetuximab monotherapy. Acneiform rash most
commonly occurred on the face, upper chest, and back but could extend
to the extremities and was characterized by multiple follicular- or
pustular-appearing lesions. Skin drying and fissuring were common in
some instances, and were associated with inflammatory and infectious
sequelae (e.g., blepharitis, cellulitis, cyst). Two cases of S. aureus
sepsis were reported. The onset of acneiform rash was generally within
the first two weeks of therapy. Although in a majority of the patients
the event resolved following cessation of treatment, in nearly half of
the cases, the event continued beyond 28 days.
Nail Disorder
A related nail disorder, occurring in 14% of patients (0.4% Grade 3),
is characterized as a paronychial inflammation with associated
swelling of the lateral nail folds of the toes and fingers, with the
great toes and thumbs as the most commonly affected digits.
Infusion Reactions
In clinical trials, severe, potentially fatal infusion reactions were
reported, one leading to death. These events include the rapid onset
of airway obstruction (bronchospasm, stridor, hoarseness), urticaria,
and/or hypotension. In studies in advanced colorectal cancer, severe
infusion reactions were observed in 3% of patients receiving cetuximab
plus irinotecan and 2% of patients receiving cetuximab monotherapy.
Grade 1 and 2 infusion reactions, including chills, fever, and dyspnea
usually occurring on the first day of initial dosing, were observed in
16% of patients receiving cetuximab plus irinotecan and 19% of
patients receiving cetuximab monotherapy. A 20-mg test dose was
administered intravenously over 10 minutes prior to the initial dose
to all patients in earlier studies. The test dose did not reliably
identify patients at risk for severe allergic reactions. Severe
infusion reactions occurred with the administration of cetuximab in
approximately 3% of patients, rarely with fatal outcome (<1 in 1000).
Approximately 90% of severe infusion reactions were associated with
the first infusion of cetuximab despite the use of prophylactic
antihistamines. These reactions were characterized by the rapid onset
of airway obstruction (bronchospasm, stridor, hoarseness), urticaria,
and/or hypotension.
Pulmonary Toxicity
Interstitial lung disease (ILD) was reported in 3 of 774 (< 0.5%)
patients with advanced colorectal cancer receiving cetuximab.
Interstitial pneumonitis with non-cardiogenic pulmonary edema
resulting in death was reported in one case. Two patients had
pre-existing fibrotic lung disease and experienced an acute
exacerbation of their disease while receiving cetuximab in combination
with irinotecan. In the clinical investigational program, an
additional case of interstitial pneumonitis was reported in a patient
with head and neck cancer treated with cetuximab and cisplatin. The
onset of symptoms occurred between the fourth and eleventh doses of
treatment in all reported cases.
1.6 Translational Science
This study will aim to address future translational science questions
related to EGFR and cetuximab in skin cancers. We plan to harvest and
store tissue samples at the time of surgery through the Head and Neck
Tumor Bank already in place. These samples may be used for future
exploratory analysis of other molecular factors in CSCCHN. Presently,
while much has been learned about the relationships among EGFR,
cetuximab, and SCCHN, there is marked uncertainty regarding if and how
this biological information should be used clinically in mucosal or
cutaneous SCCHN.
1.7 Quality of Life and Function Assessments
It is now well established that cancer of the head and neck often has
profoundly debilitating effects on quality of life (QOL), function,
and performance. In a recently reported phase III trial of cetuximab
and radiation therapy (RT) for mucosal head and neck squamous cell
carcinoma (HNSCC), cetuximab did not significantly increase acute
RT-associated adverse effects (Bonner 2006). This study also found
that addition of cetuximab to RT significantly improved locoregional
control and increased overall survival without adversely affecting QOL
(Curran 2007)13.
1.7.1 Quality of Life (QOL) Assessments
Quality of life will be assessed using two validated, multidimensional
patient reported QOL measures including: the FACT HN and the
Dermatology Life Quality Index (DLQI). Both of these QOL validated
tools are currently being used by the RTOG in SCCHN trials, and the
FACT HN is being used in the UCCI Prospective Head and Neck Oncology
Comprehensive Database that is set to go live 1/1/13.
The FACT-H&N is a multidimensional, patient self-report QOL instrument
specifically designed and validated for use with head and neck cancer
patients. The FACT-HN consists of a 27-item core scale (FACT-G) and is
supplemented with a 12-item head and neck subscale targeting head and
neck related symptoms and side effects14.
The Dermatology Life Quality Index (DLQI) will be used to explore the
impact of cetuximab induced rash on quality of life. It is expected
that rash (acneiform; maculo-papular), pruritis, and other visible
consequences associated with cetuximab-induced rash will have a
significant negative impact quality of life15,16. The DLQI17 is
designed to assess the impact of a wide range of skin disease on
patient quality of life 18,19, and it is currently being used in RTOG
0920 to assess the impact of cetuximab-induced rash on QOL in mucosal
SCCHN. The DLQI consists of 10 items and covers 6 domains including
symptoms and feelings, daily activities, leisure, work and school,
personal relationships, and treatment. Response categories include
"not at all," "a little,"a lot," and "very much," with corresponding
scores of 0, 1, 2, and 3 respectively; the response "not relevant"
(and unanswered items) are scored as "0". A total score is calculated
by summing the score of all items, resulting in a maximum score of 30
and a minimum score of 0. Scale scores are calculated for each domain.
Higher scores indicate poorer HRQL (i.e., more impairment). The FACT
HN and DLQI will be administered a baseline and at 3, 12, and 24
months after the start of radiation therapy.
1.7.2 Timeframe of Assessments
These patient-reported QOL and function measures and the
clinician-assessed measures will be administered at baseline and at 3,
12, and 24 months from the start of radiation. The 3- month QOL
assessment was chosen to coincide with usual practice of seeing a head
and patient 2-3 weeks after completion of radiation therapy. This
assessment will provide the immediate impact of radiation therapy +/-
cetuximab on QOL. The 12-month QOL assessment was chosen to coincide
with usual practice of seeing a head and patient 1 year after
completion of radiation therapy. The Radiation Oncologists expect at
this time that almost all acute toxicities related to radiation will
be resolved, and they are interested in assessing the patient’s QOL at
that time. These 2 assessment time points for patient reported
outcomes are routinely used in RTOG and other head and neck studies.
PRO assessment has been added at 24 months from RT completion. That
time point was chosen because 80 to 90% of the patients who will
progress do so by 2 years. For patients who are disease free then, the
issue, it is felt,
becomes the long-term sequelae of the treatments.
2.0 OBJECTIVES
2.1 Primary Objective
To assess the 2 – year locoregional control (LRC) of cetuximab and
radiation therapy in high risk postoperative patients with cutaneous
squamous cell carcinoma of the head and neck.
2.2 Secondary Objectives
To descriptively assess the impact of the addition of cetuximab to
postoperative radiation therapy on the following:
2 year- disease-free survival (DFS) and 2 and 5 –year overall survival
(OS);
2.3 Tertiary Objectives
To assess the impact of the addition of cetuximab to postoperative
radiation therapy on the following:
Patient-reported quality of life (QOL), swallowing, xerostomia, and
skin toxicity based on head and neck specific instruments, including
the Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN) and
the Dermatology Life Quality Index (DLQI);
3.0 PATIENT SELECTION
3.1 Conditions for Patient Eligibility
3.1.1 Pathologically (histologically) proven diagnosis of cutaneous
squamous cell carcinoma of the head and neck;
3.1.2 Pathologic invasion of skeletal muscle, cartilage, bone or lymph
nodes (>N1), M0 including no distant metastases, based upon the
following minimum diagnostic workup:
3.1.2.1 General history and physical examination by a Radiation
Oncologist and/or Medical Oncologist within 2 weeks prior to
registration;
3.1.2.2 Examination by an ENT or Head & Neck Surgeon, within 8 weeks
prior to registration;
3.1.2.3 Chest CT scan (with or without contrast) or CT/PET of chest
(with or without contrast) within 8 weeks prior to registration.
3.1.3 Gross total resection of the primary tumor with curative intent
must be completed within 9 weeks of registration. This may be a
recurrent cutaneous squamous cell carcinoma of the skin, and patient
is still eligible as long as all gross disease is currently resected.
3.1.4 Zubrod performance status of 0-2 within 2 weeks prior to
registration
3.1.5 Age > 18;
3.1.6 CBC/differential obtained within 4 weeks prior to registration
on study, with adequate bone marrow function defined as follows:
3.1.6.1 Absolute granulocyte count (AGC) > 1,500 cells/mm3;
3.1.6.2 Platelets > 100,000 cells/mm3;
3.1.6.3 Hemoglobin > 8.0 g/dl (Note: The use of transfusion or other
intervention to achieve Hgb > 8.0 g/dl is acceptable).
3.1.7 Adequate hepatic function, defined as follows:
3.1.7.1 Total bilirubin < 2 x institutional ULN within 2 weeks prior
to registration;
3.1.7.2 AST or ALT < 3 x institutional ULN within 2 weeks prior to
registration.
3.1.8 Negative serum pregnancy test within 2 weeks prior to
registration for women of childbearing potential;
3.1.9 The following assessments are required within 2 weeks prior to
the start of registration: Na, K, Cl, glucose, Ca, Mg, and albumin.
Note: Patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may
receive corrective magnesium supplementation but should continue to
receive either prophylactic weekly infusion of magnesium and/or oral
magnesium supplementation (e.g., magnesium oxide) at the
investigator’s discretion.
3.1.10 Women of childbearing potential and male participants who are
sexually active must agree to use a medically effective means of birth
control;
3.1.11 Patients must provide study specific informed consent prior to
study entry, including consent for optional tissue submission
3.2 Conditions for Patient Ineligibility
3.2.1 Prior invasive malignancy unless disease free for a minimum of 3
years; noninvasive cancers (For example, carcinoma in situ of the
breast, oral cavity, or cervix are all permissible) are permitted even
if diagnosed and treated < 3 years ago. Prior basal cell carcinoma and
squamous cell carcinoma of the skin is allowed. Patients with a
history of T1-2, N1, M0 resected differentiated thyroid carcinoma are
considered eligible.
3.2.2 Prior systemic chemotherapy or anti-EGF therapy for the study
cancer or for a different prior cancer;
3.2.3 Prior radiotherapy to the region of the study cancer that would
result in overlap of radiation therapy fields;
3.2.4 Severe, active co-morbidity, defined as follows:
3.2.4.1 Unstable angina and/or congestive heart failure requiring
hospitalization within 6 months prior to registration;
3.2.4.2 Transmural myocardial infarction within 6 months prior to
registration;
3.2.4.3 Acute bacterial or fungal infection requiring intravenous
antibiotics at the time of registration;
3.2.4.4 Chronic Obstructive Pulmonary Disease exacerbation or other
respiratory illness requiring hospitalization or precluding study
therapy at the time of registration;
3.2.4.5 Idiopathic pulmonary fibrosis or other severe interstitial
lung disease that requires oxygen therapy or is thought to require
oxygen therapy within 1 year prior to registration;
3.2.4.6 Hepatic insufficiency resulting in clinical jaundice and/or
coagulation defects; note, however, that laboratory tests for
coagulation parameters are not required for entry into this protocol.
3.2.4.7 Acquired Immune Deficiency Syndrome (AIDS) based upon current
CDC definition; note: HIV testing is not required for entry into this
protocol. The need to exclude patients with AIDS from this protocol is
necessary because the treatments involved in this protocol may be
significantly immunosuppressive. Protocol-specific requirements may
also exclude immuno-compromised patients.
3.2.4.8 Grade 3-4 electrolyte abnormalities (CTCAE, v. 4.03):
*
Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75
mmol/L) or > 12.5 mg/dl (> 3.1 mmol/L) despite intervention to
normalize levels;
*
Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14mmol/L);
*
Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23
mmol/L) despite intervention to normalize levels;
*
Potassium < 3.5 mmol/L or > 6 mmol/L despite intervention to
normalize levels;
*
Sodium < 130 mmol/L or > 155 mmol/L despite intervention to
normalize levels.
3.2.5 Pregnancy or women of childbearing potential and men who are
sexually active and not willing/able to use medically acceptable forms
of contraception; this exclusion is necessary because the treatment
involved in this study may be significantly teratogenic.
3.2.6 Prior allergic reaction to cetuximab.
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT
4.1 Required Evaluations/Management
Baseline QOL and functional assessments prior to the start of
treatment: the Functional Assessment of Cancer Therapy-Head & Neck
(EORTC HN35); the Dermatology Life Quality Index (DLQI);
4.2 Highly Recommended Evaluations/Management
4.2.1 Evaluation for prophylactic gastrostomy tube placement
(especially if the patient is > 10% below ideal body weight) within 4
weeks prior to the start of treatment;
4.2.2 EKG within 8 weeks prior to the start of treatment.
4.2.3 Banking of tumor tissue and blood in the UCCI Head and Neck
Tumor Bank is highly encouraged but not required for protocol
enrollment.
5.0 Registration Procedures
Patients are registered by contacting the University of Cincinnati
Clinical Trials Office at 513-584-7698. Patients must be registered
prior to initiation of any protocol therapy.
6.0 RADIATION THERAPY
Protocol treatment must begin within 3 weeks after registration.
6.1 Dose Specifications
The prescribed radiotherapy dose will be 60-66 Gy in 2 Gy once-daily
fraction size (total of 30-33 fractions). Radiotherapy should begin on
a Monday, Tuesday or Wednesday. The daily dose of 2 Gy will be
prescribed such that 95% of the PTV volume receives at least 95% of
prescribed dose. The spinal cord dose may not exceed 45 Gy to any
volume larger than 0.03 cc.
6.2 Technical Factors
Treatment Planning/Delivery: Megavoltage energy photon beam
irradiation is required, but may also include electron therapy as
necessary to include superficial disease areas. 3D conformal or IMRT
treatment planning may be may be used, and treatment verification
films must be taken a least once weekly.
6.3 Localization, Simulation, and Immobilization
6.3.1 Patients must have an immobilization device (e.g., aquaplast
mask) made prior to treatment planning CT scan.
6.3.2 All patients will undergo CT simulation for treatment planning.
The treatment planning CT scan may be completed with or without IV
contrast. The treatment planning CT scan must be performed with the
immobilization device and in the treatment position. Slice thickness
should be 0.3 cm or less.
6.4 Target and Normal Tissue Volume Restrictions
6.4.1 Definition of Target Volumes
6.4.1.1 CTV60: This volume will receive 2 Gy per day. CTV60 will
include the primary tumor bed (based on preoperative imaging,
preoperative physical exam/endoscopy, operative findings, pathologic
findings) plus the post-operative neck. This volume may include the
skin. It is recognized that after surgery, there can be considerable
distortion of normal anatomy. If possible, preoperative GTV(s) should
be fused onto the postoperative radiation therapy planning CT scan,
and appropriate margins added for microscopic spread (1.5-2 cm).
CTV60 also will include the ipsilateral pathologically positive
hemineck (if both sides of the neck are proven pathologically
positive, CTV60 will include both sides). This generally means
encompassing nodal levels 2a, 3, and 4 for all cases. Nodal levels 1,
2b, 5a, and 5b are included in CTV60 in selected circumstances. For
questions, contact the Principal Investigator, Dr. Mierzwa.
6.4.1.2 CTV56: This will include all other regions felt to be at risk
for harboring microscopic cancer that do not meet the criteria for
CTV60. For example, this would apply to the contralateral hemineck
being irradiated electively for a midline primary cancer. This volume
will receive approximately 1.85- 2 Gy per day.
6.4.1.3 CTV66 Optional: This may be defined at the discretion of the
treating radiation oncologist. This would include a region or regions
felt to be at especially high risk for recurrence (e.g., an area of
very close margin of resection or nodal extracapsular extension). This
area will be receiving a daily fraction size of 2- 2.2 Gy and thus,
the volume of CTV66 should be kept as small as possible.
6.4.1.4 Planning Target Volumes (PTVs): In general, the PTV should not
go outside of the skin surface; if it does exceed the skin surface,
the application of bolus material over this portion of the PTV may be
considered to treat skin to full dose.
6.4.1.4.1 PTV Expansion The minimum CTV-to- PTV expansion is 3 mm (a
larger expansion may be necessary for a target volume subject to
significant intra-fraction variability, such as the non-immobilized
oral tongue). In general, the CTV-to-PTV expansion should not exceed
10 mm.
6.4.2 Definition of Normal Tissues/Organs at Risk (OARs)- adapted from
RTOG 1016
6.4.2.1 Spinal Cord: The cord begins at the cranial-cervical junction
(i.e., the top of the C1 vertebral body). Superior to this is
brainstem and inferior to this is cord. The inferior border of the
spinal cord is at approximately T3-4 (i.e., just below the lowest
slice level that has PTV on it). The spinal cord shall be defined
based on the treatment planning CT scan. In addition, however, a
Planning Risk Volume (PRV) spinal cord shall be defined. The PRVcord =
cord + 5 mm in each dimension. This is irrespective of whether or not
IGRT is used.
6.4.2.2 Brainstem: The inferior most portion of the brainstem is at
the cranial-cervical junction where it meets the spinal cord. For the
purposes of this study, the superior most portion of the brainstem is
approximately at the level of the top of the posterior clinoid. The
brainstem shall be defined based on the treatment planning CT scan. In
addition, however, a Planning Risk Volume (PRV) brainstem shall be
defined. The PRVbrainstem = brainstem + 3 mm in each dimension.
6.4.2.3 Lips and Oral Cavity: These should be contoured as 2 separate
structures as the goal is to keep the lip dose much lower than the
oral cavity dose. The definition of lips is self explanatory. The oral
cavity will be defined as a composite structure consisting of the
anterior 1⁄2 to 2/3 of the oral tongue/floor of mouth, buccal mucosa,
and palate.
6.4.2.4 Parotid Glands: Parotid glands will be defined based on the
treatment planning CT scan.
6.4.2.5 OARpharynx: This will be defined as the “uninvolved” posterior
pharyngeal wall plus adjacent constrictor muscles. This extends from
the superior constrictor region (the inferior pterygoid plates level)
to the cricopharyngeal inlet (posterior cricoid cartilage level). This
should not overlap the PTVs.
6.4.2.6 Cervical Esophagus: This will be defined as a tubular
structure that starts at the bottom of OARpharynx and extends to the
thoracic inlet.
6.4.2.7 Glottic/Supraglottic Larynx (GSL): Obviously, for patients who
have had a total laryngectomy, this structure is not applicable. This
will be defined as a “triangular prism shaped” volume that begins just
inferior to the hyoid bone and extends to the cricoid cartilage
inferiorly and extends from the anterior commissure to include the
arytenoids. This includes the infrahyoid but not suprahyoid
epiglottis.
6.4.2.8 Mandible: This includes the entire boney structure of the
mandible from TMJ through the symphysis. It is recognized that for
oral cavity cancers, this may overlap with CTVs and PTVs.
6.4.2.9 Unspecified Tissue Outside the Targets: This will be defined
as tissue located between the skull base and thoracic inlet that is
not included in either the target volumes or the normal tissues
described above.
6.5 Treatment Planning and Delivery
Dose Prescription to PTVs
As described in Section 6.1, prescribed radiotherapy dose will be 60
Gy in 2 Gy once-daily fraction size. For inverse planning IMRT, the
goal is for 95% of the PTV60 to receive 95% of 2 Gy with a minimum
dose (cold spot) of no less than 56 Gy. It is recognized that portions
of the PTV60 close to/within the skin may receive significantly less
than 56 Gy. Bolus should be considered for these cutaneous areas
deemed to be at risk for microscopic disease. Electron cones may also
be employed to provide adequate dose to PTVs which emcompass cutaneous
tissues.
For IMRT prioritization, PTV60 will be the highest priority target
structure. PTV66 and PTV56, if applicable, will be ranked in the IMRT
planning as lower priority than PTV60 although higher priority than
normal structures other than spinal cord and brain stem.
6.5.4 Dose Constraints to Normal Structures
Spinal Cord: The PRVcord (as defined in Section 6.4.2.1) should not
exceed 45 Gy to any volume in excess of 0.03 cc (approximately 3 mm x
3 mm x 3 mm). The spinal cord PRV should not exceed 50 Gy to any
volume in excess of 0.01 cc. In treatment planning, the spinal cord
PRV should be given the highest priority.
Brainstem: The PRVbrainstem (as defined in Section 6.4.2.2) should not
exceed 50 Gy to any volume in excess of 0.03 cc (approximately 3 mm x
3 mm x 3 mm). In treatment planning, the PRVbrainstem should be given
less priority than the PRVcord but more priority than the other
critical structures listed below.
Lips: Reduce the dose as much as possible unless lips involved with
primary tumor. The mean dose should be < 20 Gy. The maximum dose will
be < 30 Gy.
Oral Cavity: Reduce the dose as much as possible. The mean dose should
be < 30 Gy.
Parotid Glands: In most cases, it will be easier to spare one parotid
than the other. The treatment planning goal will be for this
individual parotid gland to receive a mean dose of < 26 Gy. Additional
planning goals may include: 1) At least 50% of one parotid will
receive < 30 Gy; and/or 2) At least 20 cc of parotid tissue (from the
combination of both glands) will receive < 20 Gy.
OARpharynx: Reduce the dose as much as possible. Some recommended (but
not mandatory) treatment goals include: 1) No more than 33% of the
OARpharynx exceeds 50 Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of
the OARpharynx exceeds 60 Gy.
Cervical Esophagus: Reduce the dose as much as possible. For oral or
oropharyngeal cancer, some recommended (but not mandatory) treatment
goals include: 1) No more than 33% of the esophagus exceeds 45 Gy; 2)
Mean dose < 35 Gy; 3) No more than 15% of the esophagus exceeds 54 Gy.
For larynx cancer, higher doses are expected and permitted. Some
recommended doses (but not mandatory) treatment goals include: 1) No
more than 33% of the esophagus exceeds 50 Gy; 2) Mean dose < 45 Gy; 3)
No more than 15% of the esophagus exceeds 60 Gy.
Glottic and Supraglottic larynx (GSL): Reduce the dose as much as
possible.
Mandible: Reduce the dose as much as possible, hot spots within the
mandible should be avoided. It is recommended that maximum dose within
the mandible be < 66 Gy. For tumors that were not clinically or
pathologically involving the mandible, the CTV should be contoured off
the mandible.
Unspecified Tissue Outside the Targets: For the typical case in which
there is no CTV66, no more than 5% of unspecified tissue can receive
greater than 58 Gy and no more than 1% or 1cc of unspecified tissue
can receive 64 Gy or more. When a boost is used to increase the dose
to high risk regions to as much as 66 Gy, these numbers can be
increased. In this case, no more than 5% of the unspecified dose
should exceed the level of the boost dose, and no more than 1% or 1 cc
should exceed the boost dose value plus 10%.
6.6 Compliance Criteria
Treatment breaks must be clearly indicated in the treatment record
along with the reason(s) for the treatment break(s). Treatment breaks,
if necessary, ideally should not exceed five treatment days at a time
and ten treatment days total. Treatment breaks should be allowed only
for resolution of severe acute toxicity and/or for intercurrent
illness and not for social or logistical reasons.
6.7 Radiation Therapy Adverse Events The descriptions and grading
scales found in the revised NCI Common Terminology Criteria for
Adverse Events (CTCAE), version 4.03 will be utilized for grading all
adverse events. Placement of a feeding tube should be recorded as
should use of a feeding tube during and after treatment (e.g., greater
than or less than 50% of nutrition by tube). Other common radiation
adverse events include: fatigue, weight loss, regional alopecia,
xerostomia, hoarseness, transient ear discomfort, and skin erythema
and desquamation within the treatment fields. Less common long-term
treatment adverse events include: hypothyroidism, loss of hearing,
chronic swallowing dysfunction requiring permanent feeding tube, and
skin/soft tissue fibrosis. Much less common radiation adverse events
include: mandibular osteoradionecrosis, and cervical myelopathy (< 1%
with restriction of spinal cord dose to max dose of 45 Gy).
7.0 DRUG THERAPY
Protocol treatment must begin within 2 weeks after registration.
7.1 Cetuximab Initial Dose (Prior to RT): Patients will receive an
initial dose of cetuximab, 400 mg/m2, intravenously (i.v.) over 120
minutes. No chemotherapy or radiation will be given this day, and the
400 mg/m2 initial dose of cetuximab will precede the first 250 mg/m2
dose of cetuximab and the first radiation treatment by at least 5 days
(the day of the loading dose is not included in these 5 days). The
infusion rate of cetuximab must never exceed 5 mL/min.
7.2 Cetuximab subsequent dosing
Cetuximab weeks 2-7 (concurrent with RT): Patients will receive
cetuximab, 250 mg/m2, intravenously (i.v.) over 60 minutes on a weekly
schedule. The infusion rate of cetuximab must never exceed 5 mL/min.
Cetuximab will be given once a week prior to RT for a total of 6 doses
concurrent with radiation therapy.
In cases of delay in the completion of radiation therapy, then the
concurrent doses of cetuximab may continue beyond week 7 without dose
interruption until radiation therapy is completed. The total of number
of cetuximab doses should not exceed 11.
7.2.1 Safety
CAUTION: Infusion reactions may occur during or following cetuximab
administration. Most infusion reactions occur with the first infusion
of cetuximab, but some patients’ first infusion reactions have been
reported following subsequent doses (a severe reaction occurred in one
patient following the 8th dose). The infusion reaction may occur
during the infusion or be delayed until any time after the infusion.
All patients will be premedicated with diphenhydramine hydrochloride,
50 mg, (or an equivalent antihistamine) by i.v. 30-60 minutes prior to
the first dose of cetuximab in an effort to prevent an infusion
reaction. At the discretion of the treating physician, dexamethasone,
20 mg, and an H2 blocker also may be administered i.v. Premedications
are recommended prior to subsequent doses, but at the Investigator’s
discretion, the dose of diphenhydramine or dexamethasone may be
reduced.
The medical staff must closely observe patients for treatment-related
adverse events, especially infusion reactions during the cetuximab
infusion and during a post-infusion observation hour. For the initial
cetuximab infusion, vital signs (blood pressure, heart rate,
respiratory rate, and temperature) should be monitored prior to the
administration of cetuximab, a half hour into the infusion, at the
completion of the infusion, and 60 minutes post the infusion in an
area with resuscitation equipment and other agents (epinephrine,
prednisone equivalents, etc.) available. A nurse must be present in
the immediate treatment area throughout the infusion and observation
period. A physician must be in close proximity to the patient
treatment area.
For subsequent infusions, vital signs should be taken pre- and
post-infusion.
7.2.1 Formulation Cetuximab is an anti-EGFR receptor humanized
chimeric monoclonal antibody. Cetuximab is expressed in SP2/0 myeloma
cell line, grown in large scale cell culture bioreactors, and purified
to a high level purity using several purification steps including
protein A chromatography, ion exchange chromatography, low pH
treatment, and nanofiltration. Cetuximab is not known to be a
vesicant.
7.2.2 Safety Precautions Appropriate mask, protective clothing, eye
protection, gloves and Class II vertical-laminar- airflow safety
cabinets are recommended during preparation and handling.
7.2.3 Preparation and Administration Cetuximab must not be
administered as an i.v. push or bolus. Cetuximab must be administered
with the use of a low protein binding 0.22-micrometer in-line filter.
Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of
cetuximab at a concentration of 2 mg/mL in phosphate buffered saline.
The solution should be clear and colorless and may contain a small
amount of easily visible white amorphous cetuximab particulates.
Cetuximab can be administered via infusion pump or syringe pump.
*
Infusion Pump:
1.
Draw up the volume of a vial using a sterile syringe attached
to an appropriate needle (a vented spike or other appropriate
transfer device may be used).
2.
Fill cetuximab into a sterile evacuated container or bag such
as glass containers, polyolefin bags (e.g., Baxter Intravia),
ethylene vinyl acetate bags (e.g., Baxter Clintec), DEHP
plasticized PVC bags (e.g., Abbott Lifecare), or PVC bags.
3.
Repeat procedure until the calculated volume has been put in
to the container. Use a new needle for each vial.
4.
Administration must be through a low protein binding
0.22-micrometer in-line filter (placed as proximal to the
patient as practical).
5.
Affix the infusion line and prime it with normal saline before
starting the infusion.
6.
Maximum infusion rate should not exceed 5 mL/min.
7.
Use 0.9% saline solution to flush line at the end of infusion.
*
Syringe Pump:
1.
Draw up the volume of a vial using a sterile syringe attached
to an appropriate needle (a vented spike may be used).
2.
Place the syringe into the syringe driver of a syringe pump
and set the rate.
3.
Administration must be through a low protein binding
0.22-micrometer in-line filter rated for syringe pump use
(placed as proximal to the patient as practical).
4.
Connect up the infusion line and start the infusion after
priming the line with cetuximab.
5.
Repeat procedure until the calculated volume has been infused.
6.
Use a new needle and filter for each vial.
7.
Maximum infusion rate should not exceed 5 mL/min.
8.
Use 0.9% saline solution to flush line at the end of infusion.
*
Cetuximab should be piggybacked to the patient’s infusion line.
Following the cetuximab infusion, a one-hour observation period is
recommended.
*
7.2.5 Storage Requirements/Stability Store vials under
refrigeration at 2 C to 8 C (36 F to 46 F). DO NOT FREEZE.
Increased particulate formation may occur at temperatures at or
below 0 C. This product contains no preservatives. Preparations of
cetuximab in infusion containers are chemically and physically
stable for up to 12 hours at 2 C to 8 C (36 F to 46 F) and up to 8
hours at controlled room temperature (20 C to 25 C; 68 F to 77 F).
Discard any remaining solution in the infusion container after 8
hours at controlled room temperature or after 12 hours at 2 to 8
C. Discard any unused portion of the vial.
7.3. Dose Modifications (adapted from RTOG 1016)
Cetuximab Dose Levels

7.3.2 Cetuximab Dose Modifications for Hematologic Adverse Events
Cetuximab will not be dose reduced or held for hematologic adverse
events, such as neutropenia, neutropenic fever, or thrombocytopenia<
50 mL/min
7.3.3 Cetuximab Dose Modifications for Non-Hematologic Adverse Events
(adapted from RTOG 0920)

Hypomagnesemia- Electrolyte repletion, principally magnesium, was
necessary in some patients treated with cetuximab and in severe cases,
intravenous replacement was required. The time to resolution of
electrolyte abnormalities is not well known, hence monitoring during
and after cetuximab treatment is recommended:

7.3.4 Management of Cetuximab Infusion Reactions (adapted from RTOG
1016)

If a patient has an infusion reaction, the infusion rate must be
decreased. If a second infusion reaction occurs at the reduced
infusion rate, the cetuximab must be stopped.
7.3.5 Cetuximab Special Instructions If cetuximab is omitted for more
than four consecutive infusions for adverse events due to cetuximab,
or for an intercurrent illness (e.g., infection) requiring
interruption of therapy, the subject should be discontinued from
further cetuximab therapy. Cetuximab doses held due to toxicity should
not be made up. If a cetuximab dose is missed for reasons unrelated to
drug toxicity, then the missed dose may be made up at the discretion
of the Medical Oncologist, at the next appropriate time point. If
adverse events prevent the administration of cetuximab, the subject
may continue to receive radiation therapy.
7.3.5.1 Management of Cetuximab Infusion Reactions Severe or life
threatening (grade 3 or 4) infusion reactions require the immediate
interruption of cetuximab therapy and permanent discontinuation from
further treatment. Appropriate medical therapy including epinephrine,
corticosteroids, intravenous antihistamines, bronchodilators, and
oxygen should be available for use in the treatment of such reactions.
Patients should be carefully observed until the complete resolution of
all signs and symptoms. In clinical trials, mild to moderate infusion
reactions were managed by slowing the infusion rate of cetuximab and
by continued use of antihistamine pre-medications (e.g.,
diphenhydramine) in subsequent doses. If the patient experiences a
mild or moderate (grade 1 or 2) infusion reaction, the infusion rate
should be permanently reduced by 50%. For grade 1 or 2 reactions
manifesting only as delayed drug fever, see below. Cetuximab should be
immediately and permanently discontinued in patients who experience
severe (grade 3 or 4) infusion reactions.
7.3.5.2 Treatment of Isolated Drug Fever In the event of isolated drug
fever, the investigator must use clinical judgment to determine if the
fever is related to the study drug or to an infectious etiology. If a
patient experiences isolated drug fever, for the next dose, pre-treat
with acetaminophen or non-steroidal anti-inflammatory agent, repeat
antipyretic dose 6 and 12 hours after cetuximab infusion. The infusion
rate will remain unchanged for future doses. If a patient experiences
recurrent isolated drug fever following pre-medication and post-
dosing with an appropriate antipyretic, the infusion rate for
subsequent dosing should be 50% of previous rate. If fever recurs
following infusion rate change, the treating Medical Oncologist should
assess the patient’s level of discomfort with the event and use
clinical judgment to determine if the patient should receive further
cetuximab.
7.3.5.3 Cetuximab-related Rash
Manifestations Rash associated with EGFR-inhibitors is a relatively
new dermatologic condition. It appears to be “acneiform” but it is NOT
considered a form of acne; rather, it is a form of folliculitis. Skin
changes may be manifested in a number of ways: erythema; follicle
based papules, which may ulcerate; pain; itching; cosmetic
disturbance; and/or nail disorders. The rash may become infected and
transform into cellulitis.
Grading of Cetuximab-induced Rash According to physician judgment, if
a patient experiences grade 3 rash, cetuximab treatment adjustments
should be made. In patients with mild and moderate skin adverse
events, cetuximab should continue without adjustment. NOTE: Rash
intensity (i.e., the size and number of papules or the level of
discomfort and extent of erythema) may be an important consideration.
However, the absolute number of lesions, without associated physical
discomfort, does not necessarily constitute a basis for a dose
reduction or delay.
Skin and nail changes should be graded as follows, with dose
modification for > grade 3 changes.


adapted from RTOG 1016

7.3.5.3.1 Drug Related Rash Management
Patients developing dermatologic adverse events while receiving
cetuximab should be monitored for the development of inflammatory or
infectious sequelae, and appropriate treatment of these symptoms
initiated. Below are suggestions for managing cetuximab- induced rash
adapted from: Perez-Soler R, Delord J, Halpern A, et al. HER1/EGFR
inhibitor-associated rash: Future directions for management and
investigation outcomes from the HER1/EGFR Inhibitor Rash Management
Forum. The Oncologist. 10:345–356, 2005.
Antibiotics: The benefit of routine antibiotics in uncomplicated
(uninfected) rash is unclear. Some clinicians have used oral
minocycline (Minocin), mupirocin (Bactroban), or topical clindamycin
(Cleocin). Rash complicated by cellulitis should be treated with
appropriate antibiotics based on clinical judgment or microbial
sensitivity analysis.
Antihistamines: Benadryl or Atarax may be helpful to control itching.
Topical Steroids: The benefit of topical steroids is unclear.
Retinoids: No data to support use. Use is not advised.
Benzoyl peroxide: Should NOT be used--may aggravate rash.
Makeup: Rash can be covered with makeup; this should not make it worse
(use a dermatologist-approved cover-up, e.g., Dermablend, or any other
type of foundation). Remove makeup with a skin-friendly liquid
cleanser, e.g., Neutrogena, Dove, or Ivory Skin Cleansing Liqui-Gel.
Moisturizers: Use emollients to prevent and alleviate the skin
dryness, e.g., Neutrogena Norwegian Formula Hand Cream or Vaseline
Intensive Care Advanced Healing Lotion.
Sunlight: It is recommended that patients wear sunscreen and hats and
limit sun exposure while receiving cetuximab as sunlight can
exacerbate any skin reactions that may occur.
Over-the-counter medications: Over-the-counter acne vulgaris
medications (e.g., benzoyl peroxide) are not advised. This rash is not
like acne vulgaris and these treatments could make it worse.
7.4 Adverse Events
The descriptions and grading scales found in the revised NCI Common
Terminology Criteria for Adverse Events (CTCAE), version 4.03. will be
utilized for AE reporting. All serious adverse events will be reported
to the IRB per institutional protocol.
8.0 TISSUE/SPECIMEN SUBMISSION
8.1 Tissue/Specimen Submission Tumor tissue and blood will be
collected from all patients. Tumor tissue will be collected at the
time of resection and will include specimens from the primary tumor
and nodal disease as available. All University of Cincinnati specimens
will be maintained in the UCCI Tumor Bank per institutional protocol,
and all University of Michigan specimens will be maintained. Tissue
and blood submission is encouraged but not required for protocol
enrollment.
8.2 Buccal swab collection
For University of Michigan patients, buccal swabs will be collected
from the area within the anticipated radiation field pre-cetuximab
(between days -7 to 0), after the first dose of cetuximab (between
days 3 and 7), and during radiotherapy (between days 22 and 30).
Specimens will be collected as follows: After subject rinses his/her
mouth with water, buccal cells (mucosal cells), will be scraped using
sterile Cell Lifter (Manufacturer: CORNING LIFE SCIENCES PLASTIC
3008).
In order to obtain enough cells for analysis of proteins, cell lifer
will be twirled 3-4 times gently. Total time will be about 20-30
seconds. The cells will be collected from the cell lifter into 50 ml
sterile collection tube containing ice cold 5 ml of sterile PBS with
protease and phosphatase inhibitor. These collection tubes will be
transported to research laboratory located in Med Sci I (Room # 4311)
on ice as soon as possible. The swabs will be transfer to freezer
until testing.
Objective of Study:
1.
Deep sequencing of DNA from normal and tumor specimen to identify
driver oncogenes in given patient.
2.
Analyze pharmacodynamic changes in the normal tissue collected
before and during (total 3 time points/patient) radiotherapy for
driver molecules identified by DNA sequencing using high density
immunoblotting.
Correlate findings from objective 1 and 2 with clinical outcome in
terms of toxicity and response
9.0 PATIENT ASSESSMENTS
9.1 Study Parameters:
Gross total resection/surgical pathology (for post-operative patients)
or biopsy (for definitive patients) must be completed within 7 weeks
prior to registration.
A general history & physical by a Radiation Oncologist and/or Medical
Oncologist must be done within 2 weeks prior to registration, and an
examination by an ENT or Head & Neck Surgeon must be done within 8
weeks prior to registration per routine standard of care.
9.2 Evaluation During Radiotherapy
A general history & physical by a Radiation Oncologist and/or Medical
Oncologist must be done weekly per routine standard of care.
Patients must have CBCw/diff, CMP, and Mg every other week during
radiation therapy per routine standard of care for cetuximab
administration.
Biopsy of any lesion(s) suspicious for tumor recurrence is urged.
9.3 Evaluation in Follow Up
A history and physical by one of the following: a Radiation
Oncologist, Medical Oncologist, an ENT, or a Head and Neck Surgeon
must be performed at 1 and 3 months post-XRT, then q3 months for 2
years, every 6 months for 3 years, then annually for a total of 5
years. This is required for study entry and is chosen as it coincides
with standard of care practice in follow-up for head and neck cancers.
This should include a complete head and neck and cutaneous exam and
review of systems focusing on head and neck, cutaneous and pulmonary
complaints.
QOL and functional assessments (the Functional Assessment of Cancer
Therapy-Head & Neck (EORTC HN35); the Dermatology Life Quality Index
(DLQI)) will be performed at Month 3, Month 12 and Month 24.
Chest imaging (at minimum a chest x-ray or chest CT or CT/PET of
chest) is required once per year for a total of 5 image sets (or 5
years). This is per standard of care routine follow-up.
Biopsy of any lesion(s) suspicious for tumor recurrence is at the
discretion of the treating physician.
9.4 Outcomes Criteria
No evidence of disease (NED): All patients must have not measurable
tumor following surgery. Local-Regional Relapse: Recurrent cancer in
the tumor bed and/or neck not clearly attributable to a second primary
neoplasm; both imaging and biopsy confirmation are recommended but not
required. LRR will be further subdivided into three subcategories:
In-Field Local-Regional Relapse- Review of the imaging of the
local-regional relapse and the patient’s previous RT treatment data
reveals that the “epicenter” of the local-regional relapse is within
CTV60 and received an estimated dose of at least 50 Gy.
Marginal Local-Regional Relapse- Review of the imaging of the
local-regional relapse and the patient’s previous RT treatment data
reveals that the “epicenter” of the local-regional relapse was “near”
CTV60. This is defined as an estimated dose to this region that is
between 20 and 50 Gy.
Out-of-Field Local-Regional Relapse- Review of the imaging of the
local-regional relapse and the patient’s previous RT treatment data
reveals that the “epicenter” of the local-regional relapse was not
near CTV60 or CTV56 and received an estimated dose < 20 Gy.
Distant Relapse: For clinical evidence of distant metastases (lung,
bone, brain, etc.); biopsy is required. A solitary lung mass/nodule
should be considered a second primary upper aerodigestive neoplasm
unless proven otherwise.
Second Primary Neoplasm: All second primary neoplasms will be biopsy
proven with documentation of specific histology. Modified rigorous
criteria for a second primary (below) have been adapted from the
definition by Warren and Gates (1932).
A distinct lesion separated from the primary tumor site by > 2 cm of
normal epithelium; a new cancer with different histology; Any cancer,
regardless of head and neck mucosal subsite, occurring 5 or more years
after initial treatment; In the lung, new primary tumors, if squamous
cell cancer, must have histologic findings of dysplasia or CIS.
Second Primary Upper Aerodigestive Neoplasm: The emergence of a new,
invasive malignancy in the upper aerodigestive tract as a second
primary should be documented. These neoplasms include lung cancer,
esophageal cancer (including GE junction cancer), or 2nd primary head
and neck cancer that is clearly remote from the index cancer.
9.5 Quality of Life and Functional Assessments
The assessments will be completed prior to the start of cetuximab
(baseline) and at 3, 12, and 24 months from the end of RT.
9.5.1 The Functional Assessment of Cancer Therapy-Head & Neck (FACT
HN) is a multidimensional, patient-self report quality of life (QOL)
instrument specifically designed and validated for use with head and
neck patients.
9.5.2 The Dermatology Life Quality Index (DLQI) consists of 10 items
and covers 6 domains including symptoms and feelings (e.g., felt
itchy, sore, painful, embarrassed), daily activities, leisure, work
and school, personal relationships, and treatment.
9.6 Criteria for Discontinuation of Protocol Treatment
Reasons for discontinuation of protocol treatment will include
unacceptable toxicity, patient withdrawal of consent, progression of
disease or development of a second primary malignancy. In the event
that a patient discontinues protocol treatment, follow-up and data
collection will continue as specified in the protocol.
9.7 Off study criteria
Reasons for patient discontinuation of study include completion of
study follow-up, death or lost to withdrawal of patient consent
(including patients lost to follow-up). A patient may withdraw consent
partially or fully at any time during the study. Partial withdrawal of
consent will be defined as patient refusal to continue protocol
therapy while continuing to consent to follow-up on study. Full
withdrawal of consent will be defined as refusal of any further
participation in the study.
10.0 Statistical Considerations
This is a Phase II trial to characterize the 2 year loco-regional
control of patients with locally advanced cutaneous squamous cell
carcinomas of the head and neck treated with post-operative
radiotherapy and cetuximab. Our secondary goal is to characterize the
oncologic and quality of life outcomes associated with this treatment.
Cetuximab has previously been given safely in conjunction with head
and neck radiotherapy for mucosal squamous cell carcinoma in multiple
phase III trials, and so Phase I data is not necessary here. Patients
receiving at least 80% of the radiotherapy dose prescribed will be
considered to have completed protocol therapy. Patients who complete
therapy but become non-evaluable for toxicity before the
post-treatment observation period ends will be counted as evaluable in
the final analysis, and weighted in statistical analyses by the
proportion of the 18-week toxicity observation period for which they
were evaluable.
Patient accrual is projected to be 20-25 cases per year based on
current estimates of the number of patients with locally advanced
CSCCHN diagnosed/treated annually at the University of Cincinnati and
the University of Michigan. Otolaryngology billing records from
University of Michigan suggest that 65-75 patients annually undergo
resection of locally advanced cutaneous squamous cell carcinoma and
all would be potential trial candidates. It is expected that this
trial will be open to accrual for 24-36 months.
This is a Simon 2-stage design with 40 patients in stage 1 and an
additional 70 in stage 2. The null hypothesis is 0.65 LRC at 2 years
and the alternative is 0.78 LRC at 2 yrs. An interim analysis will be
performed after 40 patients are accrued and the first 20 patients have
had 2 years of potential follow-up. Kaplan-Meier estimates will be
used to determine futility. The trial may go on to accrue a total of
110 patients.
The sample size of 110 (40 form the University of Cincinnati and 70
for the patients begins with the hypothesis that the use of concurrent
cetuximab and radiotherapy post-operatively improves 2 year
loco-regional control (LRC) compared to radiotherapy alone. Using
Simon’s optimal two stage design with locoregional control as the
primary efficacy point, 2 year loco-regional control for patients with
locally advanced CSCCHN has historically been 55-70 % with resection
and post-operative radiotherapy alone at 2 years, with 5 year overall
survival of approximately 40-55% and median survival of 20-25 months.
In the multi-center, randomized trial of mucosal SCCHN by Bonner et
al., the additional of cetuximab to radiotherapy increased 2 yr LRC
from 41 to 50% and correspondingly increased 5 yr OS from 36 to 45%.
Based on these results, our target loco-regional control would be 78%
based on the University of Cincinnati experience achieving 65%
loco-regional control with post-operative RT alone. We would reject
the null hypothesis if greater than if Kaplan Meier curves estimated
greater than 72% loco-regional control.
Initial statistical design was formed with the help of Jareen
Meizen-Derr, PhD, MPH in the Division of Biostatistics and
Epidemiology at CCHMC. Data collection would be completed by the UCCI
Clinical Trials Office and data analysis would be completed by a
biostatistician within the Department of Radiation Oncology. Changchun
Xie, PhD in the Dept of Epidemiology and Biostatistics will be the
statistician analyzing data for this trial going forward at the
University of Cincinnati. The trial will also be opened at the
University of Michigan, and oversight for this multi-institutional
trial will be provided by the University of Cincinnati Cancer
Institute Clinical Trials Office.
Loco-regional control and overall survival will be estimated by the
Kaplan-Meier method.
Definitions of Endpoints
2 year LRC will be defined as the absence of tumor appearance in the
primary site or neck within 2 years, as assessed and documented
through clinical exam and imaging completed q3 months by treating
physicians during the follow-up period. Loco-regional recurrence
should be confimed by biopsy when possible, and the precise location
documented (primary site versus neck).
2 yr DFS will be defined as absence of loco-regional recurrence or the
development of metastatic disease within 2 years, as assessed by q3
month clinical exam and annual chest imaging. Distant metastases
should be biopsied when possible, and a solitary spicualted lung
nodule is considered a second primary neoplasm unless proven
otherwise. 2 and 5 year OS will be defined as the absence of death
from any cause during those time periods.
The QOL analysis is the change of QOL score on the FACT-HN and DLQI
from baseline to the 3, 12 and 24-month intervals. The mean summary
score and standard deviation of these scales will be calculated and
the mean change summarized for each time point.
11. Data and Safety Monitoring
An internal DSMB at the University of Cincinnati will oversee the
conduct of this study; this DSMB will be constituted as part of the
UCCI clinical trials infrastructure. The DSMB will be comprised of 3
external reviewers, 1 internal reviewer and 1 independent statistician
nominated by the UCCI administration. Monitoring by the DSMB will be
performed on a regular basis as defined by the UCCI DSMB charter. The
DSMB will review the study on a twice yearly basis (projected accrual
is at least 20 patients annually). The DSMB will be provided feedback
on a regular basis, including findings from adverse-event reports, and
recommendations derived from data and safety monitoring, and members
of the DSMB will have no personal or financial stake in the study.
Interim reports will be prepared twice each year by the PI with the
help of the study coordinator 1 month prior to DSMB meeting for DSMB
review. These reports will contain information about the accrual rate
with projected completion date for the accrual phase, exclusion rates
and reasons, pretreatment characteristics of patients accrued,
compliance rate of treatment delivered with respect to the protocol
prescription, and the frequency and severity of adverse events. All
serious adverse events will be reported by the PI to the DSMB and IRB
within 48 hours of occurrence.
HIPAA confidentiality will be maintained during the phases of the
trial including monitoring, preparation of interim results, review,
and response to monitoring recommendations. Exceptions may be made
under circumstances where there are serious adverse events or when it
is deemed appropriate for patient safety. The DSMB will function in an
advisory capacity and recommendations that emanate from monitoring
activities will be reviewed by the responsible official (the principal
investigator) and addressed.
References
1 AJCC staging manual 2010
2
 O’Brien, CJ, McNeil, EB, McMahon, JD, et al (2002) Significance of
clinical stage, extent of surgery and pathologi findings in metastatic
cutaneous squamous cell carcinoma of the parotid gland. Head Neck.
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3 Audet, N, Palme, CE, Gullane, P. (2004) Cutaneous metastatic
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4 Marcen, R, Pascual, J, Tato, AM, et al. (2003) Influence of
immunosuppression on the prevalence of cancer after kidney
transplatiation. Transplant Proc. 35: 1714-6.
5 Smith, KJ, Hamza, S, Skelton, H. (2004) Histologic features in
primary cutaneous squamous cell carcinoma in immunocompromised
patients focusing on organ trnasplanttation. Dermatol Surg. 30:
634-41.
6 Hinerman, RW, Indelicato, DJ, Amdur, RJ, et al. Cutaneous Squamous
Cell Carcinoma Metastatic to Parotid-Area Lymph Nodes. Laryngoscope.
118:1989-96.
7 Givi, B, Andersen, PE, Diggs, BS, et al. (2011) Outcome of patients
treated surgically for lymph node metastases from cutaneous squamous
cell carcinoma of the head and neck. Head Neck. 10:999-1004.
8 Wang, JT, Palme, CE, Morgan, GJ, et al. (2011) Predictors of outcome
in patients with metastatic cutaneous head and neck squamous cell
carcinoma involving cervical lymph nodes. Head Neck, epub ahead of
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9 Bonner, JA, Harari, PM, Giralt, J, et al. (2010) Radiotherapy plus
cetuximab for locoregionally advanced head and neck cancer: 5-year
survival data from a phase 3 randomised trial, and relation between
cetuximab-induced rash and survival. Lancet Oncol. 11:21-8.
10 Vermorken JB, Trigo J, Hitt R, et al. (2007) Open-label,
uncontrolled, multicenter phase II study to evaluate the efficacy and
toxicity of cetuximab as a single agent in patients with recurrent
and/or metastatic squamous cell carcinoma of the head and neck who
failed to respond to platinum-based therapy. J Clin Oncol.; 25:
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11 Vermorken JB, Mesia R, Rivera F, et al. (2008) Platinum-based
chemotherapy plus cetuximab in head and neck cancer. NEJM.
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12 Maubec, E, Petrow, P, Scheer-Senyarich, I (2011) Phase II study of
cetuximab as first line single drug therapy in patients with
unresectable squamous cell carcinoma of the skin. J Clin Onc. 29(25):
3419-26.
13 Curran D, Giralt J, Harari PM, et al. (2007) Quality of life in
head and neck cancer patients after treatment with high- dose
radiotherapy alone or in combination with cetuximab. J Clin Oncol.
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14 Cella DF, Tulsky DS, Gray G, et al. (1993) The functional
assessment of cancer therapy scale: Development and validation of the
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15 Boone SL, Rademaker A, Liu D, et al (2007) Impact and management of
skin toxicity associated with anti-epidermal growth factor receptor
therapy: Survey results. Oncology. 72(3-4):152-9.
16 Agero AL, Dusza SW, Benvenuto-Andrade C, et al. (2006) Dermatologic
side effects associated with the epidermal growth factor receptor
inhibitors. J Am Acad Dermatol. 55(4):657-70.
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