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13.4.2 follow-up requirements for early

Subjects who prematurely withdraw due to toxicity or progressive disease will be followed for six months after a subject is removed from the study. End of study requirements outlined above will be conducted. Subjects withdrawn for pregnancy will be followed until the pregnancy is ended.  
13.5 **End of Treatment**
The end of treatment will occur when the patient comes off of study for the following reasons:
completion of all study tests/procedures (approximately 24 months following completion of RT), progressive disease, unacceptable toxicity, allergic reaction to chemotherapy, allergic reactions to BMX-001, non-compliance with study follow-up, or withdrawal of consent. Patients will be followed for a minimum of 30 days after End of Treatment, and also followed for any unresolved adverse events considered related to study therapy. Patient death due to progressive disease will not be reported as a SAE.
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13.6 end of study

The study will be considered complete once enrollment has been met, follow-up procedures on all subjects have been conducted, and data analysis is concluded. The study may also be terminated early for any reason by the PI or sponsor. In order to terminate the study, all data extraction and analysis must be complete. Therefore, if any articles for publication are derived from the current study, they must be submitted and accepted with no further need for additional data review prior to termination with the IRB.  
Subjects that are lost to follow-up will be documented in the patient record and in the study database. In the study database, the subject will be marked as "Patient Status Unknown," along with a corresponding explanation, if any. This status may also be documented on the "Off Study Form" in the study database.
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13.6.1 early study termination

This study can be terminated at any time for any reason by the PI or sponsor. If this occurs, all subjects on study should be notified as soon as possible. Additional procedures and/or follow up should occur in accordance with this protocol.
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13.7 outcomes criteria 13.7.1 time-to-event

Progression-free survival (PFS) is defined as the time between initiation of protocol treatment and the first recurrence of disease or death.  
Overall survival will be defined as the time to death from the time of study enrollment.
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13.7.2 radiographic response

Scans will be performed according to standard of care, which commonly would include screening or baseline, 3 months ± 2 weeks from the end of radiation therapy, and then 12 months ± 1 month from the end of radiation therapy. As part of this study protocol, the 12month imaging (+/- 1-month post completion of radiation therapy or BMX-001 treatment) will be a chest x-ray that is required for research purposes.  
The guidelines and criteria for radiographic response may be based on the RECIST 1.1 criteria and apply only to patients receiving definitive intent treatment:
- Complete Response: Disappearance of all enhancing tumor - Partial Response: Greater than or equal to a 30% reduction in the size (sum of the largest perpendicular diameters) for all enhancing lesions taking as reference the baseline sum
- Progressive disease: At least a 20% increase in the size (sum of the largest perpendicular diameters) for all enhancing lesions, taking as reference the smallest sum recorded since the treatment started or the appearance of one or more new lesions
- Stable Disease: Evaluations that do not meet criteria for CR, PR or PD - Not Assessable: Progression has not been documented and one or more sites have not been assessed.
If RECIST reads are not obtained per SOC per the institution, then imaging reads per the institutional standard of practice are acceptable.
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risks of the chest x-ray

Subjects will be exposed to radiation from the required chest X-ray. The amount of radiation from a chest X-ray is low - even lower than exposure through natural sources of radiation in the environment. The average dose of the chest x-ray is about 0.1 mSv (millisieverts) and the average annual effective dose of background radiation is about 3 mSv [61].
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13.8 quality of life and

The assessments of quality of life and function (XeQoLs, OMWQ-HN, DLQI, FACT-HN, and PROCTCAE HN) will be completed at the following time points: pre-treatment, end of treatment
(during week 8) and at SOC visits following the end of therapy (this will include, at minimum, 1 month, 6 and 12 months ± 1 month after treatment). Target windows for data collection will be:
1) for end of treatment should be collected within 1 month of the last day of radiation therapy; and 2) at 6 and 12 months should be collected within ± 1 month of these time-points. However, if not possible, data should still be collected outside of these windows and analysis will account for the timing of data collection.  
PRO-CTCAE HN: In addition to traditional physician obtained QoL parameters, we will incorporate a modification of the PRO-CTCAE which is a new outcome measure recently developed by the NCI designed to capture the patient's self-report of adverse events [60]. A
subset of items drawn from the PRO-CTCAE system have been aggregated into a head and neck specific tool for use in this trial (PRO-CTCAE HN). The PRO-CTCAE HN measure tailored for use in this study consists of 25 items that evaluate the presence and/or severity of a range of symptoms, as well as the degree to which the symptom/toxicity interferes with usual function.  
Individuals respond to the questionnaire items using a 5-point Likert scale. PRO-CTCAE HN is designed to be completed by the patient without assistance from research staff similar to other quality of life measures.  
All QoL/functional assessments listed below will be collected from patients at clinic visits via case report forms or by electronic data collection at the discretion of each clinical institution.  
All quality of life questionnaires should be completed, even if the patient stops protocol treatment.
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14 safety monitoring and reporting

The PI is responsible for the identification and documentation of adverse events and serious adverse events, as defined below. PI will review and sign off on all adverse events and problems as they occur and will report them to the IRB in accordance with HRPP policies. At each study visit, the PI or designee must assess, through non-suggestive inquiries of the subject or evaluation of study assessments, whether an AE or SAE has occurred.
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14.1 adverse events

An adverse event (AE) is any untoward medical occurrence in a subject receiving study drug and which does not necessarily have a causal relationship with this treatment. For this protocol, the definition of AE also includes worsening of any pre-existing medical condition. An AE can therefore be any unfavorable and unintended or worsening sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of BMX-001, whether or not related to use of the BMX-001. Abnormal laboratory findings without clinical significance (based on the PI's judgment) should not be recorded as AEs, but laboratory value changes that require therapy or adjustment in prior therapy are considered adverse events.  
From the time the subject signs the informed consent form through the End of Treatment visit (as defined in the section titled End of Treatment), all AEs must be recorded in the subject medical record and adverse events case report form.  
AEs will be assessed according to the CTCAE version 4.03. If CTCAE grading does not exist for an AE, the severity of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening
(4), or fatal (5).  
Attribution of AEs will be indicated as follows:  
- Definite: The AE is clearly related to the study drug - Probably: The AE is likely related to the study drug - Possible: The AE may be related to the study drug - Unlikely: The AE is doubtfully related to the study drug - Unrelated: The AE is clearly NOT related to the study drug
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14.1.1 reporting of aes

BioMimetix JV, LLC, should be notified of all treatment-related adverse events on a regular basis
(to be agreed upon by the study team and BioMimetix JV, LLC).  
14.2 **Serious Adverse Events**
An AE is considered "serious" if in the opinion of the investigator it is one of the following outcomes:
- Fatal - Life-threatening - Constitutes a congenital anomaly or birth defect - A medically significant condition (defined as an event that compromises subject safety or may require medical or surgical intervention to prevent one of the three outcomes above).  
- Requires inpatient hospitalization or prolongation of existing hospitalization. - Results in persistent or significant incapacity or substantial disruption to conduct normal life functions.
Reports of these should be made to Elizabeth Regan, MD, PhD, at Elizabeth.regan@bmxpharma.com, or 303-921-1880 (cell) with the Clinical Trial Manager on carbon copy.
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14.2.1 reporting of saes

Only adverse events that the Sponsor determines to be serious, unanticipated, and related or possibly/probably (i.e., more likely than not) related to the research must be reported to the appropriate IRB. Those adverse events will be submitted in the applicable IRB and sponsor, according the following guidelines:
- Report within 24 hours of learning about any subject's death that was unanticipated and more likely related to the research than unrelated;
- Report within 5 business days of learning about any serious, unanticipated, and related or possibly/probably related adverse event; that was more likely related to the research than unrelated.  
- Report within 10 business days of learning about any other SAE that does not meet the above criteria.
The Sponsor must report to the FDA, in an IND safety report, any suspected adverse reaction that is both serious and unexpected. Before submitting this report, the sponsor needs to ensure that the event meets all three of the definitions contained in the requirement:
- Suspected adverse reaction (i.e., there is a reasonable possibility that the drug caused the adverse event)
- Serious - Unexpected If the adverse event does not meet all three of the definitions, it should not be submitted as an expedited IND safety report. The Sponsor is required to report to the FDA all IND Safety reports in writing within 15 days (7 days for unexpected fatal or life-threatening suspected adverse reaction). The FDA Form 3500A can be found on the FDA website, www.fda.gov. All other adverse events will be reported to the FDA in the Annual Report.  
The sponsor is responsible for safety reporting to the FDA and for compliance with all applicable laws and regulations pertaining to adverse events. To ensure patient safety each study treatment-related serious adverse event will also be reported to BioMimetix JV, LLC, within 24 hours by the Principal Investigator. Follow-up information on these events shall also be reported to BioMimetix JV, LLC, within 24 hours. Follow-up information may include hospital admission records, discharge summaries and autopsy reports, where applicable.  
In addition, the Principal Investigator shall also make an accurate report to the reviewing Institutional Review Board (IRB) on any serious and unexpected AE per local guidelines.
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14.3 external data and safety

The sponsor and Principal Investigators are responsible for overseeing the safety and efficacy of the trial, executing the DSM plan, and complying with all reporting requirements to local and federal authorities. Additional oversight will be carried out by an external DSMB.  
An external DSMB will be utilized to monitor the Phase 1/Phase 2 clinical trial of BMX-001. This DSMB will be organized to meet requirements of Western IRB, the institutional IRBs, and the NCI. We anticipate a charter with a minimum of 3 members, which may include: a radiation oncologist, a medical oncologist both with expertise in head and neck cancer, a biostatistician, and/or an ethicist or patient advocate. The DSMB will hold an initial meeting to review the final protocol before enrollment of the first patient. The responsibilities of the DSMB will be to review safety of study procedures, to maintain study integrity, to review adverse events and to review efficacy of the outcome data. The DSMB will meet either face to face or by teleconference at least semi-annually and on an ad hoc basis as indicated by any adverse events.  
Minutes will be kept of both open and closed meetings of the DSMB. At the end of the study, all minutes taken will be available to the clinical trial principal investigators, the NCI, and BioMimetix JV, LLC.  
During Phase 2 of the trial, the sponsor will notify the DSMB within 48 hours of any reported grade 3- 5 DLT deemed probably or definitely related to BMX-001.  
The DSMB's responsibilities will include evaluation of treatment outcome for evidence of tumor protection by the study drug. If the DSMB determines that there is substantial evidence of excess tumor progression in the presence of the study drug, the DSMB will have authority to recommend closure of the clinical trial.
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14.4 monitoring

BioMimetix JV, LLC, will be responsible for oversight of monitoring the trial per the trial monitoring plan and will conduct monitoring visits to ensure subject safety and to ensure that the protocol is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, good clinical practice, and applicable regulatory requirements. Monitoring visits will be conducted in compliance with FDA regulations (21CFR812), SOPs, and GCP/ICH (5.18) guidelines to ensure the integrity of the data reported is accurate and the safety, rights, and well-being of the subjects are protected. The clinical trial will be monitored while the trial is active and is enrolling and overseeing patients.  
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or for cause. Every reasonable effort will be made to maintain confidentiality during study monitoring.
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14.5 audits

The clinical centers may conduct internal audits to evaluate compliance with the protocol and the principles of GCP. The PIs agree to allow auditors direct access to all relevant documents and to allocate his/her time and the time of the study team to the auditors in order to discuss findings and any relevant issues. The primary purpose of the audit is to verify that the standards for safety of human subjects in clinical trials and the quality of data produced by the clinical trial research are met. The audit will serve as a quality assurance measure, internal to the institution. Additional goals of such audits are to detect both random and systemic errors occurring during the conduct of clinical research and to emphasize "best practices" in the research/clinical trials environment.
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15 data management and processing

Study documentation includes but is not limited to source documents, case report forms, monitoring logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, and regulatory documents that can be found in the studyspecific regulatory binder, which includes but is not limited to signed protocol and amendments, approved and signed informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution records.  
Source documents are original records that contain source data, which is all information in original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source documents include but are not limited to hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial. When possible, the original record should be retained as the source document. However, a photocopy is acceptable provided that it is a clear, legible, and an exact duplication of the original document.
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15.2 case report forms (crfs)

The electronic CRF (eCRF) will be the primary data collection document for the study and is developed in conjunction with statistical oversight. The CRFs will be updated in a timely manner following acquisition of new source data. Only the staff appropriately delegated by the PI are permitted to make entries, changes, or corrections in the eCRF.  
An audit trail will be maintained automatically by an electronic CRF management system. All users of this system will complete user training, as required or appropriate per regulations.
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15.3 data management procedures and

Completeness of entered data will be checked automatically by the eCRF system, and users will be alerted to the presence of data inconsistencies. Additionally, the data management team and the statistical team will cross-reference the data to verify accuracy. Missing or implausible data will be highlighted for the PI requiring appropriate responses (i.e., confirmation of data, correction of data, completion or confirmation that data is not available, etc.).  
The database will be reviewed and discussed prior to database closure and will be closed only after resolution of all remaining queries. An audit trail will be kept of all subsequent changes to the data.
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15.4 coding

All medical terms will be coded using CTCAE v.4.03, which has been harmonized to MedDRA
(Medical Dictionary for Regulatory Activities) coding. Medication will be coded according to the World Health Organization Drug Dictionary.  
15.5 **Study Closure**
Following completion of the studies, the PI will be responsible for ensuring the following activities:
- Data clarification and/or resolution; - Accounting, reconciliation, and destruction/return of used and unused study drugs; - Review of site study records for completeness; - Shipment of all remaining laboratory samples to the designated laboratories; - Submitting closure report to IRB.  
15.6 **Records Retention**
The Principal Investigator will maintain study-related records for the longer of a period of:
- at least two years after the date on which a New Drug Application is approved by the FDA, as an IND is involved;
- at least two years after formal withdrawal of the IND associated with this protocol, as an IND is involved;
- per institutional guidelines.
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16 statistical methods and data

All statistical analysis will be performed under the direction of Christopher Wichman, Ph.D.,
University of Nebraska Medical Center (UNMC). Any data analysis carried out independently by the investigator must be approved by the lead statistician before publication or presentation.  
All patients who receive protocol treatment are expected to be included in all statistical analyses. In Phase 1, cohorts of 3 patients will be treated starting with dose level \#1 and ending with dose level \#2. Once three patients have undergone treatment without experiencing DLT
after a monitoring period of four weeks, the dose of the subsequent group of 3 patients will be escalated. Phase 1
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16.1.1 analysis sets

All patients who receive protocol treatment are expected to be included in all statistical analyses.  
For purposes of determining dose escalation, we expect that all patients will be included in analyses with the possible exception of those patients receiving treatment who refuse to return for assessment and for whom information concerning toxicity cannot be garnered from other sources (e.g., primary care physician, family members, etc).  
For adverse events, overall survival and progression free survival, all patients who receive BMX001 will be included in the summaries of adverse events.  
For HRQoL, all patients who receive BMX-001 will be included in the analysis with the possible exception of those patients receiving treatment who refuse to return for assessment and for whom HRQoL data are not available.
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16.1.2 patient demographics and other

The clinical and sociodemographic characteristics of all patients treated will be summarized using descriptive statistics (e.g., means/standard deviations, percentiles, frequencies). Patient characteristics within patient subgroups defined by dose level will also be generated.
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16.1.3 treatments

The number of patients treated at each dose level will be summarized.
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16.1.4 phase 1 dose escalation

The primary objective of this Phase 1 study is to determine the maximum tolerated dose safety and toxicity profile of BMX-001 administered in conjunction with standard radiotherapy and cisplatin among patients with newly diagnosed head and neck cancer. Two dose levels were completed: 1) 7 mg/subject and 2) 14 mg/subject followed by maintenance doses given twice weekly of 1) 3.5 mg/subject and 2) 7 mg/subject. The toxicity profile will be done using the CTCAE version 4.03.
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16.1.5.2 mtd

The MTD has been selected for studying in Phase 2 based on completed Phase 1 human trials of BMX-001.
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16.1.5.3 secondary objectives of phase

Adverse events will be tabulated in a different manner for the manuscript summarizing the results of this study, annual reports for the Safety Oversight Committee, and the final report included within ClinicalTrials.gov.  
For the manuscript, adverse events that are possibly, probably, and definitely treatmentrelated will be summarized. For each type of toxicity, the maximum grade experienced by each patient will be summarized with frequency distributions within each treatment group.  
For ClinicalTrials.gov, serious adverse events and other adverse events will be summarized separately. These tabulations will reflect the number of patients who experience each type of toxicity regardless of grade or attribution.  
CTCAE data will be collected and compared:  
1. To assess the effect of BMX-001 in combination with RT and concurrent cisplatin in newly diagnosed HNSCC patients on overall survival (OS), progression free survival
(PFS), and initial response to treatment.
Kaplan-Meier methods will be used to graphically describe the distribution of overall survival (OS) and progression-free survival. OS is defined as the time interval between initiation of protocol treatment and death, with overall survival censored at last follow-up if the patient remained alive. PFS is defined as the time between initiation of protocol treatment and disease progression or death. If the patient remains alive without disease progression, then PFS will be censored at last followup. Median OS and PFS, as well as 6- and 12-month estimates of OS and PFS, will be estimated from the Kaplan-Meier curve.  
2. To examine the impact on mucositis of BMX-001 in combination with RT and concurrent cisplatin in treatment of newly diagnosed patients with locally advanced head and neck cancers by evaluating the degree of oral mucositis at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, the duration of oral mucositis, and evaluation of mucositis-related patient-reported outcomes.
The duration of mucositis at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be descriptively summarized using means and 95% confidence intervals (CIs). The evaluation of mucositis-related patient-reported outcomes at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be descriptively summarized using frequencies, percentages, and 95% CIs.  
3. To examine the impact on xerostomia of BMX-001 in combination with RT and concurrent cisplatin by evaluating degree of xerostomia at 30-39 Gy, 40-49 Gy, 5059 Gy, and 60-70 Gy, the duration of xerostomia, and evaluation of xerostomiarelated patient-reported outcomes.
The duration of xerostomia at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be descriptively summarized using means and 95% confidence intervals (CIs). The evaluation of xerostomia-related patient-reported outcomes at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be descriptively summarized using frequencies, percentages, and 95% CIs.  
4. To examine the impact on radiation dermatitis of BMX-001 in combination with RT
and concurrent cisplatin by evaluating degree of radiation dermatitis at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, the duration of radiation dermatitis, and evaluation of radiation dermatitis-related patient-reported outcomes.
The duration of radiation dermatitis at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be descriptively summarized using means and 95% confidence intervals (CIs). The evaluation of radiation dermatitis-related patient-reported outcomes at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be descriptively summarized using frequencies, percentages, and 95% CIs.  
5. To characterize the single-dose and repeated-dose pharmacokinetic profiles of BMX-001 when delivered in combination RT and concurrent cisplatin.
16.1.5.4 Exploratory Objectives for Phase 1 **Study**
The mean change between baseline and each follow-up assessment for HRQoL will be descriptively summarized using means and 95% CIs.  
16.2 **Phase 2**
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16.2.1 primary endpoint

1) The primary endpoint is incidence of severe oral mucositis (grade 3 and 4).  
The incidence rates of severe oral mucositis graded by CTCAE as grade 3 or 4 will be descriptively summarized and calculated.  
2) The secondary endpoints are:
1. Median duration (days) of severe oral mucositis 2. Median time (days) to onset of severe oral mucositis 3. Incidence of grade >/= 2 Xerostomia at month 1 and 6 post completion of RT.
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16.2.2 objectives/endpoint and data analyses

16.2.2.1 Primary Objectives **for Phase 2**
1. To confirm the safety and tolerability of the MTD of BMX-001 in conjunction with RT and concurrent cisplatin in cohort of HNSCC patients.
The incidence rates of adverse events (AE) will be described without regard to causality. AE incidence occurring within each cycle will be described. The frequency of overall toxicity, categorized by toxicity grades, will also be summarized. Listings of laboratory results collected at baseline and during the study will be generated and descriptive statistics summarizing changes in laboratory tests over time will be presented. Adverse events will be tabulated in a different manner for the manuscript summarizing the results of this study, annual reports for the Safety Oversight Committee, and the final report included within ClinicalTrials.gov For the manuscript, adverse events that are possibly, probably, and definitely treatment-related will be summarized. For each type of toxicity, the maximum grade experienced by each patient will be summarized with frequency distributions within each treatment group.  
For ClinicalTrials.gov, serious adverse events and other adverse events will be summarized separately. These tabulations will reflect the number of patients who experience each type of toxicity regardless of grade or attribution.  
2. To further explore efficacy based on the impact of BMX-001 on mucositis, xerostomia, and radiation dermatitis in treatment of newly diagnosed patients with locally advanced head and neck cancers by evaluating the degree of these adverse events at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, the duration of the adverse events, and evaluation of related patientreported outcomes. Comparison against historical controls will be made.  
The duration of mucositis, xerostomia and radiation dermatitis, separately, at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be descriptively summarized using means and 95% confidence intervals (CIs). The evaluation of mucositis, xerostomia, and radiation dermatitis, separately, at related patient-reported outcomes at 30-39 Gy, 40-49 Gy, 50-59 Gy, and 60-70 Gy, will be descriptively summarized using frequencies, percentages, and 95%
CIs.  
16.2.2.2 Secondary **Objectives for Phase 2**
1. To assess the efficacy based upon overall survival (OS), median progression free survival (PFS), and initial response to treatment
Kaplan-Meier methods will be used to graphically describe the distribution of overall survival (OS) and progression-free survival. OS is defined as the time interval between initiation of protocol treatment and death, with overall survival censored at last follow-up if the patient remained alive. PFS
is defined as the time between initiation of protocol treatment and disease progression or death. If the patient remains alive without disease progression, then PFS will be censored at last follow-up. Median OS and PFS,
as well as 6- and 12-month estimates of OS and PFS will be estimated from the Kaplan-Meier curve.  
2. To assess radiographic response in locally advanced HNSCC patients treated with standard RT and cisplatin with BMX-001 at MTD. The radiographic response (CR or PR) will be assessed as defined in 12.6.2.  
The radiographic response rate will be tabulated and reported using frequencies and 95% confidence intervals.
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16.2.2.3 exploratory objectives for phase

1. To further describe patient-reported outcomes of HRQoL in locally advanced HNSCC with standard RT, cisplatin, and BMX-001 at the MTD.
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16.2.3 interim analysis for phase

No interim efficacy analyses are planned given the length of time to assess an individual patient's outcome and the expected rapidity of patient accrual.
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16.2.4 sample size calculation for

In this study, patients will receive BMX-001 at the Recommended Phase 2 Dose (RP2D). The ultimate goal of this study is to determine whether BMX-001 in combination with standard RT and cisplatin treatment is worthy of further investigation. The cohort will be compared with historical controls, which will be assessed for quality.  
We will focus on the occurrence and severity of mucositis, xerostomia, and radiation dermatitis in this power calculation given that the study is not a randomized study, even though we are interested in comparing groups with respect to change in mucositis and xerostomia between protocol timepoints.  
We anticipate accruing 48 patients which, for statistical purposes, we assume that approximately 40 will have available measurements of mucositis, xerostomia, and radiation dermatitis. We use a conservative estimate of a proportion of 0.50 since it results in the widest CI. A sample size of 40 produces a two-sided 95% exact confidence interval (Clopper-Pearson)
with a width equal to 0.324 when the sample proportion is 0.50.
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17 references

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Vujaskovic Z, Batinic-Haberle I. Antiangiogenic action of redox-modulating Mn(III) mesotetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+), via suppression of oxidative stress in a mouse model of breast tumor. Free Radic Biol Med 2009; 47(7):992-1004.  
15. Lee MY, Wang Y, Vanhoutte PM. Senescence of cultured porcine coronary arterial endothelial cells is associated with accelerated oxidative stress and activation of NFkB. J Vasc Res 2010; 47(4):287-98.  
16. Khan I, Batinic-Haberle I, Benov LT. Effect of potent redox-modulating manganese porphyrin, MnTM-2-PyP, on the Na(+)/H(+) exchangers NHE-1 and NHE-3 in the diabetic rat. Redox Rep 2009; 14(6):236-42.  
17. Batinic-Haberle I, Reboucas JS, Spasojevic I. Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential. Antioxid Redox Signal 2010; 13(6):877-918.  
18. Li H, Wang Y, Pazhanisamy SK, Shao L, Batinic-Haberle I, Meng A, Zhou D. Mn(III) meso-tetrakis-
(N-ethylpyridinium-2-yl) porphyrin mitigates total body irradiation-induced long-term bone marrow suppression. Free Radic Biol Med 2011; 51(1):30-7.  
19. Ashcraft KA, Boss MK, Tovmasyan A, Roy Choudhury K, Fontanella AN, Young KH, Palmer GM,
Birer SR, Landon CD, Park W, Das SK, Weitner T, Sheng H, Warner DS, Brizel DM, Spasojevic I,
Batinic-Haberle I, Dewhirst MW. Novel manganese-porphyrin superoxide dismutase-mimetic widens the therapeutic margin in a preclinical head and neck cancer model. Int J Radiat Oncol Biol Phys. 2015 Nov 15;93(4):892-900. doi: 10.1016/j.ijrobp.2015.07.2283. Epub 2015 Jul 29.  
20. Garofalo MC, Ward AA, Farese AM, Bennett A, Taylor-Howell C, Cui W, Gibbs A, Prado KL,
MacVittie TJ. A pilot study in rhesus macaques to assess the treatment efficacy of a small molecular weight catalytic metalloporphyrin antioxidant (AEOL 10150) in mitigating radiationinduced lung damage. Health Phys 2014; 106(1):73-83.  
21. Sheng H, Enghild JJ, Bowler R, Patel M, Batinić-Haberle I, Calvi CL, Day BJ, Pearlstein RD, Crapo JD, Warner DS. Effects of metalloporphyrin catalytic antioxidants in experimental brain ischemia.  
Free Radic Biol Med 2002; 33(7):947-61.  
22. Bao F, Liu D. Hydroxyl radicals generated in the rat spinal cord at the level produced by impact injury induce cell death by necrosis and apoptosis: protection by a metalloporphyrin. Neuroscience 2004; 126(2):285-95.  
23. Ling X, Liu D. Temporal and spatial profiles of cell loss after spinal cord injury: Reduction by a metalloporphyrin. J Neurosci Res 2007; 85(10):2175-85.  
24. Liu D, Bao F, Prough DS, Dewitt DS. Peroxynitrite generated at the level produced by spinal cord injury induces peroxidation of membrane phospholipids in normal rat cord: reduction by a metalloporphyrin. J Neurotrauma 2005; 22(10): 1123-33.  
25. Moeller BJ, Dreher MR, Rabbani ZN, Schroeder T, Cao Y, Li CY, Dewhirst MW. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 2005; 8(2):99-110.  
26. Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med 2011; 365(6):537-47.  
27. Schreck R, Albermann K, Baeuerle PA. Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun 1992; 17(4):221-37.  
28. Koga F, Yoshida S, Tatokoro M, Kawakami S, Fujii Y, Kumagai J, Neckers L, Kihara K. ErbB2 and NFkappaB overexpression as predictors of chemoradiation resistance and putative targets to overcome resistance in muscle-invasive bladder cancer. PLoS One 2011; 6(11):e27616.  
29. National Comprehensive Cancer Network. Head and Neck Cancers (Version 1.2015).  
http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed September 19, 2015.  
30. Gilbert M, Armstrong T, Meyers C. Issues in assessing and interpreting quality of life in patients with malignant glioma. Semin Oncol 2000; 27(3 Suppl 6):20-6.  
31. Liu R, Page M, Solheim K, Fox S, Chang SM. Quality of life in adults with brain tumors: current knowledge and future directions. Neuro Oncol 2009; 11(3):330-9.  
32. Cella, D.F. Manual: Functional Assessment of Cancer Therapy (FACT) Scales and Functional Assessment of HIV Infection (FAHI) Scale. Chicago: Rush-Presbyterian-St. Luke's Medical Center, 1994.  
33. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P,
Brannon J, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993; 11:570-9.  
34. D'Antonio LL, Zimmerman GJ, Cella DF, Long SA. Quality of life and functional status measures in patients with head and neck cancer. Archives of Otolaryngol Head & Neck Surgery 1996; 122:482-487 35. Brucker PS, Yost K, Cashy J, Webster K, Cella D. General population and cancer patient norms for the Functional Assessment of Cancer Therapy-General (FACT-G). Evaluation & the Health Professions 2005; 28(2):192-211.  
36. Murphy BA, Ridner S, Wells N, Dietrich M. Quality of life research in head and neck cancer: a review of the current state of the science. Crit Rev Oncol/Hematol 2007; 62(3):251-267.  
37. Jensen K, Jensen AB, Grau C. The relationship between observer-based toxicity scoring and patient assessed symptom severity after treatment for head and neck cancer. A correlative cross sectional study of the DAHANCA toxicity scoring system and the EORTC quality of life questionnaires. Radiotherapy and Oncology 2006; 78(3):298-305.  
38. List MA, D'Antonio LL, Cella DF, Siston A, Mumby P, Haraf D, Vokes E. The performance status scale for head and neck cancer patients and the functional assessment of cancer therapy-head and neck (FACT-H&N) scale: A study of utility and validity. Cancer 1996; 77:2294-2301 39. http://www.facit.org/
40. Epstein JB, Beaumont JL, Gwede CK, Murphy B, Garden AS, Meredith R, Le Q-T, Brizel D, Isitt J,
Cella D. Longitudinal evaluation of the oral mucositis weekly questionnaire-head and neck cancer, a patient-reported outcomes questionnaire. Cancer 2007; 109:1914–1922.  
41. Eisbruch A, Kim HM, Terrell JE, Marsh LH, Dawson LA, Ship JA. Xerostomia and its predictors following parotid-sparing irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 2001; 50(3):695-704.  
42. Eisbruch A, Ship JA, Dawson LA, Kim HM, Bradford CR, Terrell JE, Chepeha DB, Teknos TN,
Hogikyan ND, Anzai Y, Marsh LH, Ten Haken RK, Wolf GT. Salivary gland sparing and improved target irradiation by conformal and intensity modulated irradiation of head and neck cancer.  
World J Surg 2003; 27 (7): 832-7.  
43. Hensen BS, Inglehart MR, Eisbruch A, Ship JA. Preserved salivary output and xerostomia-related quality of life in head and neck cancer patients receiving parotid-sparing radiotherapy. Oral Oncol 2001; 37(1):84-93.  
44. Hurt CN, Nixon LS, Griffiths GO, Al-Mokhtar R, Gollins S, Staffurth JN, Phillips CJ, Blazeby JM,
Crosby TD. SCOPE1: a randomised phase II/III multicentre clinical trial of definitive chemoradiation, with or without cetuximab, in carcinoma of the oesophagus. BMC Cancer 2011; 11(1):1.  
45. RTOG 0920: A Phase III Study of Postoperative Radiation Therapy (IMRT) /- Cetuximab for Locally-Advanced Resected Head and Neck Cancer." Accessed February 19, 2016. https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0920.  
46. Habl G, Potthoff K, Haefner MF, Abdollahi A, Hassel JC, Boller E, Indorf M, Debus J. Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (Head and neck cancer:
ImmunoChemo and Radiotherapy with Erbitux) - a multicenter phase IV trial. BMC Cancer 2013; 13(1):345.  
47. Potthoff K, Habl G, Bruckner T, Suppan C, Hassel J, Jäger D, Indorf M, Debus J. Randomized controlled trial to evaluate the effects of ethyl-2-cyanoacrylate on pain intensity and quality of life in head and neck cancer patients suffering from cetuximab-induced rhagades during radioimmunotherapy: the support trial. BMC Cancer 2014; 14(1), 270.  
48. Lewis V, Finlay AY. 10 years experience of the Dermatology Life Quality Index (DLQI). Journal of Investigative Dermatology Symposium Proceedings 2004; 9(2):169-180.  
49. Basra MKA, Fenech R, Gatt RM, Salek MS, Finlay AY. The Dermatology Life Quality Index 1994–
2007: a comprehensive review of validation data and clinical results. Br J Dermatol 2008; 159(5):997-1035.  
50. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical measure for routine clinical use. Clin Exper Dermatol 1994; 19(3):210-216.  
51. Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, Xu F, Yassine M. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28(8):1351-57.  
52. Trzaska SM. Cisplatin. C&EN News June 2005; 83(25). FDA Oncology Tools Approval Summary for Cisplatin for Metastatic Ovarian Tumors. Food and Drug Administration, Center for Drug Evaluation and Research. 19 December 1978. Archived from the original on 8 February 2008.  
http://web.archive.org/web/20080208232952/http://www.accessdata.fda.gov/scripts/cder/onc tools/summary.cfm?ID=73. Retrieved 19 Nov 2013.  
53. Loehrer PJ, Einhorn LH. Drugs five years later. Cisplatin. Ann Intern Med 1984; 100(5):704–13.  
54. Milosavljevic N, Duranton C, Djerbi N, Puech PH, Gounon P, Lagadic-Gossmann D, DimancheBoitrel MT, Rauch C, Tauc M, Counillon L, Poët M. Nongenomic effects of cisplatin: acute inhibition of mechanosensitive transporters and channels without actin remodeling. Cancer Res 2010; 70(19):7514-22.  
55. Milosavljevic N, Duranton C, Djerbi N, Puech PH, Gounon P, Lagadic-Gossmann D, DimancheBoitrel MT, Rauch C, Tauc M, Counillon L, Poët M. Nongenomic effects of cisplatin: acute inhibition of mechanosensitive transporters and channels without actin remodeling. Cancer Res 2010; 70(19):7514-22.  
56. Milosavljevic N, Duranton C, Djerbi N, Puech PH, Gounon P, Lagadic-Gossmann D, DimancheBoitrel MT, Rauch C, Tauc M, Counillon L, Poët M. Nongenomic effects of cisplatin: acute inhibition of mechanosensitive transporters and channels without actin remodeling. Cancer Res 2010; 70(19):7514-22.  
57. Windsor RE, Strauss SJ, Kallis C, Wood NE, Whelan JS. Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma: A pilot study. Cancer 2012; 118(7):1856–67.  
58. Levi JA, Aroney RS, Dalley DN. Haemolytic anaemia after cisplatin treatment. Br Med J (Clin Res Ed) 1981; 282(6281):2003-4.  
59. Ross AD, Sheng H, Warner DS, Piantadosi CA, Batinic-Haberle I, Day BJ, Crapo JD. Hemodynamic effects of metalloporphyrin catalytic antioxidants: structure-activity relationships and species specificity. Free Radic Biol Med 2002; 33(12):1657-69.  
60. Hay JL, Atkinson TM, Reeve BB, Mitchell SA, Mendoza TR, Willis G, Minasian LM, Clauser SB,
Denicoff A, O'Mara A, Chen A, Bennett AV, Paul DB, Gagne J, Rogak L, Sit L, Viswanath V, Schrag D, Basch E; NCI PRO-CTCAE Study Group. Cognitive interviewing of the US National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Qual Life Res. 2014 Feb; 23(1):257-69.  
61. Mettler FA, et al. "Effective Doses in Radiology and Diagnostic Nuclear Medicine: A
Catalog," *Radiology* (July 2008), Vol. 248, pp. 254–63.
schema of clinical trial
appendix a functional assessment of

Below is a list of statements that other people with your illness have said are important. Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
GPI
G72 cc CIN GPS
G76 GPT GSI
052 s GS4 oss GS6 QI
057  
| Not                                                            | A little   | Some-    | Quite   | Very   |      |
|----------------------------------------------------------------|------------|----------|---------|--------|------|
| PHYSICAL WELL-BEING                                            | at all     | bit      | what    | a bit  | muum |
| I have a lack of energy                                        | 2          |          |         |        |      |
| 0                                                              | l          | 3        | 4       |        |      |
| I have nausea                                                  | 0          | 1        | 2       | 3      | 4    |
| Because of my physical condition, I have trouble               |            |          |         |        |      |
| meeting the needs of my family .                               | 1          | 2        | 3       |        |      |
| 0                                                              | 4          |          |         |        |      |
| I have pain                                                    | 0          | 1        | 2       | 3      | 4    |
| I am bothered by side effects of treatment .                   | 2          |          |         |        |      |
| 0                                                              | 1          | 3        | 4       |        |      |
| I feel ill .                                                   | 0          | 1        | 2       | 3      | 4    |
| I am forced to spend time in bed .                             | 0          | 1        | 2       | 3      | 4    |
| SOCIAL/FAMILY WELL-BEING                                       | Not        | A little | Some-   | Quite  | Very |
| at all                                                         | bit        | what     | a bit   | muh    |      |
| I feel close to my friends .                                   | 2          |          |         |        |      |
| 0                                                              | 1          | 3        | 4       |        |      |
| I get emotional support from my family .                       | 0          | 1        | 2       | 3      | 4    |
| I get support from my friends.                                 | 0          | 1        | 2       | 3      | 4    |
| My family has accepted my illness                              | 0          | 1        | 2       | 3      | 4    |
| I am satisfied with family communication about my              | 2          |          |         |        |      |
| illness.                                                       | 0          | 1        | 3       | 4      |      |
| I feel close to my partner (or the person who is my main       |            |          |         |        |      |
| support) .                                                     | 0          | i        | 2       | 3      | 4    |
| Regardless of your current level of sexual activity, please    |            |          |         |        |      |
| answer the following question. If you prefer not to answer it, |            |          |         |        |      |
| please mark this box and go to the next section.               |            |          |         |        |      |
| I am satisfied with my sex life                                | 0          | 1        | 2       | 3      | 4    |  
| GEI   |
|-------|
| GE2   |
| GE3   |
| GE    |
| CES   |
| CL6   |  
FACT-H&N (Version 4)
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
Very much CP1 CF2 Fi G4  
| EMOTIONAL WELL-BEING                                          | Not   | . A little   | Some-   | Quite   | Very   |
|---------------------------------------------------------------|-------|--------------|---------|---------|--------|
| at all                                                        | bit   | what         | a bit   | much    |        |
| I feel sad .                                                  | 0     | 2            | 3       |         |        |
| 1                                                             | 4     |              |         |         |        |
| I am satisfied with how I am coping with my illness ......... | 0     | 1            | 2       | 3       | 4      |
| 2                                                             | 3     |              |         |         |        |
| I am losing hope in the fight against my illness              | 0     | 1            | 4       |         |        |
| I feel nervous .                                              | 0     | i            | 2       | 3       | 4      |
| I worry about dying                                           | 0     | 1            | 2       | 3       | 4      |
| I worry that my condition will get worse .                    | 2     | 3            |         |         |        |
| 0                                                             | 1     | 4            |         |         |        |  
ES FF
E
4  
| FUNCTIONAL WELL-BEING                                                    | Not   |
|--------------------------------------------------------------------------|-------|
| at all                                                                   |       |
| I am able to work (include work at home) .............................   | 0     |
| My work (include work at home) is fulfilling .                           | 0     |
| I am able to enjoy life.                                                 | 0     |
| I have accepted my illness                                               | 0     |
| I am sleeping well .                                                     | 0     |
| I am enjoying the things I usually do for fun .......................... | 0     |
| I am content with the quality of my life right now...............        | 0     |  
4 4 4 4 4 4  
| A little   | Some-   | Quite   |
|------------|---------|---------|
| bit        | what    | a bit   |
| 1          | 2       | 3       |
| 2          |         |         |
| 1          | 3       |         |
| 1          | 2       | 3       |
| 1          | 2       | 3       |
| 2          | 3       |         |
| 1          |         |         |
| 1          | 2       | 3       |
| i          | 2       | 3       |
schema of clinical trial
fact-h&n (version 4)

Please circle or mark one number per line to indicate your response as it applies to the past 7 davs.  
| davs.                                        | ACT-H&N (Version                               |          |       |       |      |    |
|----------------------------------------------|------------------------------------------------|----------|-------|-------|------|----|
| ADDITIONAL CONCERNS                          | Not at                                         | A little | Some- | Quite | Very |    |
| all                                          | bit                                            | what     | a bit | much  |      |    |
| I am able to eat the foods that I like .     |                                                |          |       |       |      |    |
| HANT                                         | 0                                              | 1        | 2     | 3     | 4    |    |
| My mouth is dry                              |                                                |          |       |       |      |    |
| HAN                                          | 0                                              | l        | 2     | 3     | 4    |    |
| HRN                                          | I have trouble breathing .                     | 0        | 1     | 2     | 3    | 4  |
| My voice has its usual quality and strength  | 0                                              | 1        | 2     | 3     | 4    |    |
| I am able to eat as much food as I want      | 2                                              |          |       |       |      |    |
| 0                                            | l                                              | 3        | 4     |       |      |    |
| I am unhappy with how my face and neck look. | 0                                              | 1        | 2     | 3     |      |    |
| HRN                                          | 4                                              |          |       |       |      |    |
| HRN                                          | I can swallow naturally and easily .           | 0        | 1     | 2     | 3    | 4  |
| HANI                                         | I smoke cigarettes or other tobacco products . | 0        | l     | 2     | 3    | 4  |
| I drink alcohol (e.g. beer, wine, etc.).     | 2                                              |          |       |       |      |    |
| HRN                                          | 0                                              | 1        | 3     | 4     |      |    |
| EER
10                                              | I am able to communicate with others .         | 0        | 1     | 2     | 3    | 4  |
|                                              | I can eat solid foods.                         | 0        | 2     |       |      |    |
| 1                                            | 3                                              | 4        |       |       |      |    |
| PER
19                                              | I have pain in my mouth, throat or neck .      | 0        | 1     | 2     | 3    | 4  |
| rork at 1                                    |                                                |          |       |       |      |    |  
content with the quality English (Universal)
Copyright  1987, 1997
appendix b oral mucositis weekly
omwo-hn

We are interested in some things about you and your health. Please answer all of the questions yourself by circling the number that best applies to you. There are no "right" or "wrong" answers.  
  
3. How much MOUTH AND THROAT SORENESS did you experience in the past week? ( Circle one number )  
| No soreness.             | 0   |
|--------------------------|-----|
| A little soreness.       | l   |
| Moderate soreness.       | 2   |
| Quite a lot of soreness. | 3   |
| Extreme soreness         | 4   |  
  
How much did MOUTH AND THROAT SORENESS limit you in each of the following activities during the 4.  
past week? (Circle one number on each line)  
| Not                      | Limited   | Limited   |  Limited   | Unable   |
|--------------------------|-----------|-----------|------------|----------|
| Limited                  | A Little  | A Lot     | To Do      |          |
| Some                     |           |           |            |          |
| a. Sleeping              | l         | 2         | 3          | 4        |
| b. Swallowing            | i         | 2         | 3          | 4        |
| c. Drinking              | l         | 2         | 3          | 4        |
| d. Eating                | l         | 2         | 3          | 4        |
| ee                       | l         | 2         | u          | 4        |
| f. Brushing your teeth . | 1         | 2         | 3          | 4        |  
v2 17Feb05 dms 5. On a scale from 0 to 10, how would you rate your OVERALL MOUTH AND THROAT SORENESS during the past week? (Circle one number)
7  
  
0 l 2 3 4 5 6 8 9 No Soreness Worst Possible Soreness 6. On a scale of 0 to 10, what number best describes the MOUTH PAIN that you have experienced in the past week?  
(Circle one number)
6 7 5 0 2 3 4 8  
  
9 l 10 No Pain Worst Pain Imaginable 7. On a scale of 0 to 10, what number best describes the THROAT PAIN that you have experienced in the past week? (Circle one number)
3          4 5 6 0 l 2 8 9 No Pain 10 Worst Pain Imaginable 8. Is there anything that you're going through that we haven't covered? (Please explain)  
| l    |
|------|
| l    |
| l    |
| __   |
| __   |
| __   |
| AAAA |
| __   |
| __   |  
10 W4
appendix c xerostomia-related quality of
omwo-hn

These questions are concerned with your oral health and how it affects your life. Please answer the questions by checking the box that describes best how true each statement has been for you during the past 7 days:
1.  
My mouth/throat dryness limits the kinds or amounts of food I eat.  
❏ Not at all D A little
❏ Quite a bit
❏ Very much 2.  
❏ Not at all 3.  
❏ Not at all My mouth/throat dryness causes discomfort.  
❏ A little D A little
❏ Quite a bit
❏ Very much My mouth/throat dryness causes a lot of worry or concern.  
4.  
My mouth/throat dryness keeps me from socializing (going out).  
❏ Not at all 5.  
My mouth/throat dryness makes me uncomfortable when eating in front of other people.  
❏ Not at all 6.  
❏ Not at all
□ A little
❏ A little D A little My mouth/throat dryness makes me uncomfortable speaking in front of other people.  
7.  
❏ Not at all My mouth/throat dryness makes me nervous.  
❏ A little
□ A little
❏ Quite a bit
❏ Quite a bit
❏ Very much ❏ Very much ❏ Very much
❏ Very much 8.  
My mouth/throat dryness makes me concerned about the looks of my teeth and mouth.  
Very much
❏ Not at all 9.  
❏ Not at all My mouth/throat dryness keeps me from enjoying life.  
❏ A little
❏ Very much 10.  
My mouth/throat dryness interferes with my daily activities.  
❏ Not at all
❏ A little 1.  
My mouth/throat dryness interferes with my intimate relationships.  
❏ Not at all 12.  
My mouth/throat dryness has a bad effect on tasting food.  
❏ Very much
□ A little □ A little
❏ Not at all 13.  
My mouth/throat dryness reduces my general happiness with life.  
❏ Not at all
❏ A little 14.  
❏ Quite a bit
❏ Very much
❏ Not at all My mouth/throat dryness affects all aspects of my life.  
❏ A little how would you feel about this?  
stisfied  
❏ Terrible satisfied/dissatisfied dissatisfied
❏ Quite a bit
❏ Quite a bit
❏ Quite a bit
❏ Quite a bit ❏ Quite a bit
❏ Quite a bit
❏ Quite a bit
❏ Quite a bit ❏ Quite a bit
❏ Very much
❏ Very much  
❏ Somewhat
❏ Somewhat ❏ Somewhat ❏ Somewhat ❏ Somewhat  
❏ Somewhat
❏ Somewhat ❏ Somewhat ❏ Somewhat
❏ Somewhat
❏ Somewhat ❏ Somewhat ❏ Mixed: equally 15.  
❏ Delighted
❏ Very much If you were to spend the rest of your life with your mouth/throat dryness just the way it is now,
❏ Very much
appendix d dermatology life quality
omwo-hn

DERMATOLOGY LIFE QUALITY INDEX
Hospital No:
Name:
Adress:
Date:
Diagnosis:
Score:  
  
The aim of this questionnaire is to measure how much your skin problem has affected your life OVER THE LAST WEEK. Please tick I one box for each question.  
| OVER THE LAST WEEK. Please tick I one box for each question.                                                           |                                             |                |                 |
|------------------------------------------------------------------------------------------------------------------------|---------------------------------------------|----------------|-----------------|
| 1.                                                                                                                     | Over the last week, how itchy, sore,        | Very much      | D               |
| painful or stinging has your skin                                                                                      | A lot                                       | o              |                 |
| D                                                                                                                      |                                             |                |                 |
| ben?                                                                                                                   | A little                                    |                |                 |
| Not at all                                                                                                             | o                                           |                |                 |
| 2.                                                                                                                     | Over the last week, how embarrassed         | Very much      | D               |
| or self conscious have you been because                                                                                | A lot                                       | D              |                 |
| D                                                                                                                      |                                             |                |                 |
| of your skin?                                                                                                          | A little                                    |                |                 |
| Not at all                                                                                                             | D                                           |                |                 |
| Over the last week, how much has your                                                                                  | o                                           |                |                 |
| 3.                                                                                                                     | Very much                                   |                |                 |
| skin interfered with you going                                                                                         | A lot                                       | D              |                 |
| shopping or looking after your home or                                                                                 | □                                           |                |                 |
| A little                                                                                                               |                                             |                |                 |
| garden?                                                                                                                | Not at all                                  | D              | Not relevant 🙂 |
| 4.                                                                                                                     | Over the last week, how much has your       | D              |                 |
| Very much                                                                                                              |                                             |                |                 |
| skin influenced the clothes                                                                                            | A lot                                       | D              |                 |
| you wear?                                                                                                              | A little                                    | o              |                 |
| Not at all                                                                                                             | D                                           | Not relevant □ |                 |
| 5.                                                                                                                     | Over the last week, how much has your       | Very much      | D               |
| skin affected any social or                                                                                            | A lot                                       | D              |                 |
| leisure activities?                                                                                                    | A little                                    | D              |                 |
| D                                                                                                                      | Not relevant □                              |                |                 |
| Not at all                                                                                                             |                                             |                |                 |
| 6.                                                                                                                     | Over the last week, how much has your       | Very much      | D               |
| D                                                                                                                      |                                             |                |                 |
| skin made it difficult for                                                                                             | A lot                                       |                |                 |
| you to do any sport?                                                                                                   | A little                                    | D              |                 |
| Not at all                                                                                                             | D                                           | Not relevant □ |                 |
| 7.                                                                                                                     | Over the last week, has your skin prevented | Yes            | D               |
| you from working or studying?                                                                                          | No                                          | o              | Not relevant 🙂 |
| If "No", over the last week how much has                                                                               | A lot                                       | o              |                 |
| D                                                                                                                      |                                             |                |                 |
| your skin been a problem at                                                                                            | A little                                    |                |                 |
| work or studying?                                                                                                      | Not at all                                  | o              |                 |
| 8.                                                                                                                     | Over the last week, how much has your       | Very much      | D               |
| skin created problems with your                                                                                        | A lot                                       | D              |                 |
| partner or any of your close friends                                                                                   | A little                                    | D              |                 |
| or relatives?                                                                                                          | Not at all                                  | D              | Not relevant □  |
| Very much                                                                                                              |                                             |                |                 |
| 9.                                                                                                                     | Over the last week, how much has your       | D              |                 |
| skin caused any sexual                                                                                                 | A lot                                       | o              |                 |
| d ifficulties?                                                                                                         | A little                                    | D              |                 |
| Not at all                                                                                                             | D                                           | Not relevant □ |                 |
| 10.                                                                                                                    | Over the last week, how much of a           | Very much      | o               |
| problem has the treatment for your                                                                                     | A lot                                       | o              |                 |
| skin been, for example by making                                                                                       | A little                                    | D              |                 |
| your home messy, or by taking up time?                                                                                 | Not at all                                  | D              | Not relevant □  |
| Please check you have answered EVERY question. Thank you.                                                              |                                             |                |                 |
| ©AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors. |                                             |                |                 |  
9.
appendix d dermatology life quality
appendix e pro-ctcae-hn nci pro-ctcae™️

As individuals go through treatment for their cancer they sometimes experience different symptoms and side effects. For each question, please check or mark an 😉 in the one box that best describes your experiences over the past 7 days...  
1.  
In the last 7 days, what was the SEVERITY of your DRY MOUTH at its WORST?  
O None O Mild O Moderate O Severe O Very severe 2.  
In the last 7 days, what was the SEVERITY of your DIFFICULTY SWALLOWING at its WORST?  
O None O Mild  
  
O Moderate O Severe O Very severe  
3.
In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at their  
WORST?  
  
O Very severe  
  
O None O Mild In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your usual or daily activities?  
O Not at all O A little bit O Somewhat  
  
O Quite a bit O Very much 4.  
In the last 7 days, what was the SEVERITY of SKIN CRACKING AT THE CORNERS OF
YOUR MOUTH at its WORST?  
O None  
  
  
  
O Very severe
5.  
In the last 7 days, did you have any VOICE CHANGES?  
O No  
  
O Yes
6.  
In the last 7 days, what was the SEVERITY of your HOARSE VOICE at its WORST?  
O None O Mild O Moderate O Severe O Very severe  
7.  
WORST?
In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its O Moderate O None O Mild O Severe O Very severe In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual or dily activities?  
O Not at all O A little bit O Somewhat O Quite a bit O Very much The PRO-CTCAE™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the NATIONAL AND IN THE PRO-
INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A.  Use of the PRO-CTCAE''' is subject to NCI's Terms of Use.
appendix d dermatology life quality
nci pro-ctcae™️ items item library

8.  
In the last 7 days, how OFTEN did you have NAUSEA?  
O Occasionally   O Frequently O Never O Rarely O Almost constantly In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST?  
O None O Mild O Moderate O Severe
- Very severe  
  
9.  
In the last 7 days, how OFTEN did you have VOMITING?  
O Never O Rarely O Occasionally O Frequently O Almost cnstantly  
  
In the last 7 days, what was the SEVERITY of your VOMITING at its WORST?  
O None O Mild O Moderate O Severe  
  
O Very severe 10. In the last 7 days, did you have any RASH?  
O Yes O No 1. In the last 7 days, what was the SEVERITY of your SKIN BURNS FROM RADIATION at their WORST?  
O Mild O Moderate O Not O None O Severe O Very applicable severe In the last 7 days, what was the SEVERITY of your NUMBNESS OR TINGLING IN YOUR
12.  
HANDS OR FEET at its WORST?  
O None O Mild O Moderate O Severe O Very severe In the last 7 days, how much did NUMBNESS OR TINGLING IN YOUR HANDS OR FEET
INTERFERE with your usual or daily activities?  
O Not at all O A little bit O Quite a bit O Somewhat O Very much 13. In the last 7 days, what was the SEVERITY of RINGING IN YOUR EARS at its WORST?  
O Mild O None O Moderate O Severe O Very severe The PRO-CTCAE ™ items and information herein were developed by the NATIONAL CANCER INSTITUTE at the NATIONAL
INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A.  Use of the PRO-CTCAE''' is subject to NCI's Terms of Use.  
14. In the last 7 days, how OFTEN did you have PAIN?  
O Never O Rarely  
  
  
  
In the last 7 days, what was the SEVERITY of your PAIN at its WORST?  
O None O Mild In the last 7 days, how much did PAIN INTERFERE with your usual or daily activities?  
O Not at all O A little bit O Somewhat O Quite a bit 15. In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF
ENERGY at its WORST?  
O None O Mild O Moderate O Severe O Very severe In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY
INTERFERE with your usual or daily activities?  
O Not at all O A little bit O Somewhat  
  
O Quite a bit O Very much  
  
  
  
  
O Yes
Please list any other symptoms:
The PRO-CTCAE''' Items and Information herein were developed by the NATIONAL CANCER INSTITUTE at the NATIONAL
INSTITUTES OF HEALTH, in Bethesda, Maryland, U.S.A.  Use of the PRO-CTCAE rr  is subject to NCI's Terms of Use.  
| 1.                                                               | In the last 7 days, what was the SEVERITY of this symptom at its   |            |          |        |
|------------------------------------------------------------------|--------------------------------------------------------------------|------------|----------|--------|
| WORST?                                                           |                                                                    |            |          |        |
| O None                                                           | O Mild                                                             | O Moderate | O Severe | O Very |
| severe                                                           |                                                                    |            |          |        |
| 2.                                                               | In the last 7 days, what was the SEVERITY of this symptom at its   |            |          |        |
| WORST?                                                           |                                                                    |            |          |        |
| O None                                                           | O Mild                                                             | O Moderate | O Severe | O Very |
| severe                                                           |                                                                    |            |          |        |
| 3.                                                               | In the last 7 days, what was the SEVERITY of this symptom at its   |            |          |        |
| WORST?                                                           |                                                                    |            |          |        |
| O None                                                           | O Mild                                                             | O Moderate | O Severe | O Very |
| severe                                                           |                                                                    |            |          |        |
| In the last 7 days, what was the SEVERITY of this symptom at its |                                                                    |            |          |        |
| 4.                                                               | WORST?                                                             |            |          |        |
| O None                                                           | O Mild                                                             | O Moderate | O Severe | O Very |
| severe                                                           |                                                                    |            |          |        |
| 5.                                                               | In the last 7 days, what was the SEVERITY of this symptom at its   |            |          |        |
| WORST?                                                           |                                                                    |            |          |        |
| O None                                                           | O Mild                                                             | O Moderate | O Severe | O Very |
| severe                                                           |                                                                    |            |          |        |