institution # rtog foundation 3501
7.10 serious adverse event (sae)

The treating investigator has the obligation to report all serious adverse events to RTOG and per the local IRB per institutional policy. This study will utilize the RTOG SAE Report Form for reporting of SAEs. The SAE Report Form, SAE Reporting Guidelines, and SAE Report Form Instructions are available on the RTOG web site, www.RTOG.org.  
To ensure patient safety, every SAE, regardless of suspected causality, occurring after protocolspecified procedures begin and 30 days after the patient has stopped study treatment must be reported to RTOG within the timeframe detailed in the reporting table below. Information about all SAEs is collected and recorded on a Serious Adverse Event Report Form; all applicable sections of the form must be completed in order to provide a clinically thorough report. The investigator must assess and record the relationship of each SAE to each specific study treatment (if there is more than one study treatment), complete the SAE Report Form, and e-mail the completed form to RTOG at RTOG3501AE@acr.org. RTOG will report applicable SAEs to Novartis within 24 hours of awareness.  
It is the responsibility of the investigator to document all adverse events which occur during the study. It is the responsibility of the IND holder to comply with IND safety reporting of SAEs as set forth in the Code of Federal Regulations, Section 312.32 and as IND holder, RTOG will report applicable SAEs to FDA and Novartis within the requirement timeframe 7.10.1 Reporting SAEs Any SAE regardless of relationship to protocol treatment must be reported by the investigator.  
All deaths during treatment or within 30 days following completion of protocol treatment must be reported within 5 working days. Any SAEs experienced after this 30 days period should only be reported to RTOG if the investigator suspects a causal relationship to protocol treatment; see the reporting table below for timeframes. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow up to the original episode. The SAE report should comprise a full written summary, detailing relevant aspects of the SAE in question. The SAE summary also must include the investigator's assessment of expectedness and relatedness to specific protocol treatment (e.g., radiation, cisplatin, or lapatinib). When applicable, information from relevant hospital case records and autopsy reports should be included. Initial and follow-up information, when it becomes available, should be e-mailed to RTOG3501AE@acr.org. In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to the RTOG Operations Office by phone, (14189215-574-3191). An electronic report must be submitted immediately upon re-establish of the Internet connection. RTOG will report the SAE to the FDA and to Novartis.  
SAEs brought to the attention of the investigator at any time after cessation of protocol treatment and considered by the investigator to be related or possibly related to protocol treatment also must be reported via the SAE Report Form, using the SAE Form instructions. All SAEs must be e-mailed to RTOG3501AE@acr.org **within the designated timeframe** outlined in the table below as well as the SAE Form Instructions. RTOG will complete a preliminary review of the SAE details and may contact the site with queries. RTOG then will report the SAE to the FDA and Novartis. Note: The individual completing the SAE Report Form should remain vigilant for RTOG's review and be prepared to respond to queries expeditiously in order to ensure timely reporting to the FDA and Novartis. Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse  
  
  
Events that Occur on Studies under an IND within 30 Days of the Last Administration of the Investigational Agent/Intervention1  
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
  
NOTE: Investigators **MUST** immediately report to the sponsor **ANY** Serious Adverse Events, whether or not they  
  
5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL **SERIOUS** adverse events that meet the above criteria **MUST** be immediately reported within the timeframes detailed in the table below.  
| Grade 1         | Timeframes   | Grade 3 Timeframes   | Grade 4 & 5   |
|-----------------|--------------|----------------------|---------------|
| Grade 2         |              |                      |               |
| Hospitalization | Timeframes   | Timeframes           |               |  
  
| Resulting in  Hospitalization   | 10 Calendar Days   | 24-Hour 5        |
|---------------------------------|--------------------|------------------|
| Not resulting in                | Calendar Days      |                  |
| Hospitalization                 | Not required       | 10 Calendar Days |  
  
  
  
  
o "24-Hour; 5 Calendar Days" - The AE must initially be reported within 24 hours; 5 Calendar Days; the AE must initially be reported within 24 hours of learning of the AE, followed by a complete expedited o "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar days of 1Serious adverse events that occur more than 30 days after the last administration of protocol treatment and have an attribution of possible, probable, or definite require reporting as follows: Expedited 24-hour notification followed by complete report within 5 calendar days for:
All Grade 4, and Grade 5 AEs Expedited 10 calendar day reports for:
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization Grade 3 adverse events 7.10.1.1 *Pregnancy* **(2/2/16)**  
  
Patients who become pregnant during the study should discontinue the study immediately. Investigators should report any pregnancy, including a male patient's impregnation of his partner, as a grade 3 SAE and submit an SAE report to RTOG at RTOG3501AE@acr.org. Investigators should submit the pregnancy report form within 14 days of notification. RTOG
will report the pregnancy to Novartis within 24 hours of awareness. Patients should be instructed to notify the investigator if it is determined after completion of the study that they become pregnant either during the treatment phase of the study or within five calendar days after the treatment period. Whenever possible a pregnancy should be followed to term, any premature termination reported, and the status of the mother and child should be reported after delivery to RTOG Headquarters. RTOG will report the status to Novartis.  
7.10.2 Assessment of Causality and Expectedness Every effort should be made by the investigator to explain each SAE and assess its expectedness and relationship, if any, to study drug treatment. Causality should be assessed using the following categories: no (not related), or yes (reasonable possibility).  
The determination of expectedness and the degree of certainty with which a SAE is attributed to drug treatment (or alternative causes, e.g. natural history of the underlying diseases, concomitant therapy, etc.) will be determined by how well the experience can be understood in terms of the following:
Known pharmacology of the drug Reaction of similar nature being previously observed with this drug or class of drug The event having often been reported in literature for similar drugs as drug related (e.g.  
skin rashes, blood dyscrasia)
The event being related by time to drug administration terminating with drug withdrawal
(dechallenge) or reproduced on rechallenge.
The investigator may change his/her opinion of expectedness and/or causality in light of followup information, by amending the SAE Report Form. The expectedness and causality assessment is one of the criteria used when determining regulatory reporting requirements to the FDA.
institution # rtog foundation 3501
8.0 surgery 8.1 neck dissection

A neck dissection is required for patients with persistent nodal disease, any stage, if a palpable abnormality or worrisome radiographic abnormality persists in the neck 8-9 weeks after completion of therapy. A neck dissection is optional for patients with multiple positive lymph nodes or with lymph nodes exceeding 3 cm in diameter at pre-treatment (N2a, N2b, N3) who achieve a complete clinical and radiographic response in the neck. Surgery will be performed within 2 weeks once the decision for neck dissection is made. The status of the primary tumor should be assessed thoroughly at the beginning of the surgical procedure before undertaking nodal dissection. Presence of persistent disease at the primary site, confirmed by frozen section, will be considered a failure of protocol treatment. Further treatment of such a patient will depend on the clinical situation and are at the discretion of the treating physicians.  
8.1.1 *For Patients Undergoing a Neck Dissection* Cervical lymphadenectomy will encompass the original levels of lymph node involvement, which should be removed en bloc. Preservation of the accessory nerve, jugular vein, and sternomastoid muscle is encouraged if consistent with complete removal of all residual nodal disease; however, the extent of the neck dissection will be at the discretion of the surgeon. A
selective neck dissection should be performed when feasible. At no time will synchronous bilateral radical neck dissections be performed. If bilateral radical neck dissections are necessary the neck procedure must be staged at an interval of 6 weeks between lymphadenectomies. The neck dissection specimens must be divided and oriented into discrete anatomic levels in the operating room by the supervising surgeon, and submitted for pathologic review in separate containers. Discrete groups of nodes that are matted or spaced too closely to be resolved as separate nodes under the microscope or by FDG-PET/CT (< 0.5 cm intervening distance) will be categorized as "nodal clusters." These clusters will be considered equivalent to solitary nodes to allow for simpler and more accurate categorization of all sampled tissue. An attending pathologist should oversee evaluation of all neck dissection specimens according to Appendix IV.  
8.1.2 Institutions must submit a Surgery Form (S1), a Surgical Operative Report (S2), and a Surgical Pathology Report (S5) for patients who have surgery to the primary site and/or to regional nodes post-treatment (see Section 12.1).  
8.2 Surgical Removal (Salvage) of the Primary Tumor Directed biopsies at the site of the index lesions will not be performed in the absence of suspicion for relapse. Criteria for biopsy after chemoradiation include a persistent mucosal abnormality or imaging studies that are suspicious for persistent or recurrent disease at 8-9 weeks after completion of therapy. Options for salvage therapy will depend upon the clinical situation and are at the discretion of the treating physicians. Surgical removal (salvage resection) of the primary tumor will be performed, if possible, when biopsy-proven cancer remains more than three months after completion of therapy. The nature of the surgical resection will be dictated by the extent of tumor at the initial evaluation. The operation will be conducted using accepted criteria for primary surgical treatment of the cancer.  
Tissues for pathologic evaluation of margins must be taken from the patient (rather than the surgical specimen itself). However, the specimen itself should be marked at sites corresponding to the evaluated margins in order to assess sampling error in obtaining clear margins. If gross tumor remains or when no effort to remove tumor has been made, the patient will be considered to have "gross residual disease." In the absence of residual disease, if the cancer extends to within 5 mm of a surgical margin, the patient would be considered to have "close" margins.
institution # rtog foundation 3501
9.0 other therapy 9.1 permitted

All supportive therapy for optimal medical care will be given during the study period at the discretion of the attending physician(s) within the parameters of the protocol and documented on each site's source documents as concomitant medication.
institution # rtog foundation 3501
9.2 non-permitted supportive therapy

9.2.1 Hematopoietic Growth Factors The routine use of erythropoietic growth factors (e.g. darbepoetin, erythropoietin) is strongly discouraged. Granulocytic growth factors (e.g. filgrastim) should not be used concurrently during radiation therapy, unless radiation therapy has been stopped to allow for recovery of neutropenia and fever. Radiation therapy, lapatinib/placebo, and/or cisplatin should not be resumed within 48 hours of the last dose of filgrastim.
institution # rtog foundation 3501
10.0 tissue/specimen submission (8/13/15)

NOTE: Patients must be offered the opportunity to participate in the correlative components of the study, such as tissue/specimen submission. If the patient consents to participate in the tissue/specimen component of the study, the site is required to submit the patient's specimens as specified in Section 10.0 of the protocol. Sites are not permitted to delete the tissue/specimen component from the protocol or from the sample consent.
institution # rtog foundation 3501
10.1 tissue/specimen submission

The Biospecimen Bank at the University of California San Francisco acquires and maintains high quality specimens from RTOG trials. Tissue from each block is preserved through careful block storage and processing. The RTOG encourages participants in protocol studies to consent to the banking of their tissue. The Biospecimen Bank at UCSF provides tissue specimens to investigators for translational research studies. Translational research studies integrate the newest research findings into current protocols to investigate important biologic questions. The Biospecimen Bank at UCSF also collects tissue for central pathology review. Central review of tissue can be for eligibility and/or analysis.  
In this study, pre-treatment tissue will be submitted to the Biospecimen Bank at UCSF for the purpose of central review of pathology (mandatory for eligibility for oropharyngeal patients), for banking, and for translational research (highly recommended but optional). In addition, blood will be submitted pre-treatment, at the end of radiation treatment, and at 6 months from the end of treatment for translational research (highly recommended but optional).
institution # rtog foundation 3501
if the patient consents to

For patients with oropharyngeal carcinoma, the Biospecimen Bank at UCSF will process 2 unstained sections from the tissue block and will send the sections to Dr. Adel El-Naggar who will determine HPV status by p16 immunohistochemistry within 7-10 business days. **Note**: If a specimen was previously submitted to the Biospecimen Bank at UCSF for determination of HPV
status for another RTOG trial and found to be p16 negative, investigators can forward a Specimen Transmittal (ST) Form to the Biospecimen Bank requesting that the specimen be sent to Dr. El-Naggar for central lab confirmation of p16 negativity.  
The following material must be provided to the Biospecimen Bank at UCSF for Central Review:
10.2.1 One H & E stained slide per positive biopsy site (slide can be duplicate cut stained H&E; it does not have to be the diagnostic slide);
10.2.2 A corresponding paraffin-embedded tissue block of the tumor or three paraffin-embedded 2mm punches from the same block (with an H&E of the embedded punches); Institutions that are unable to submit a tissue block for the required HPV analysis of oropharyngeal cases may instead take 4 unstained sections from the block then obtain three 2 mm core punches of the block and re-embed the core punches into a recipient paraffin block for submission (or sites can send the punches to the Biospecimen Bank to be embedded). Institutions can request an FFPE specimen plug kit (see Appendix IV) from the Biospecimen Bank at UCSF free of charge for this purpose: 415-476-7864 (7864)/FAX 415-476-5271; RTOG@ucsf.edu.
If an institution is uncomfortable with obtaining the unstained sections and punches and wants to retain the tissue block, the site can send the entire block to the Biospecimen Bank at UCSF, and the Bank will obtain the unstained sections and the core punches from the block and return the remaining block to the site. Please indicate this request (to obtain the sections, perform the core punch procedure, and return the block) on the submission form. **Note**: For oropharyngeal carcinoma patients, there is a 10-day turnaround needed for HPV assays, so institutions should send the block (or punches/slides) by overnight courier to the Biospecimen Bank as soon as possible with their request.  
If an institution is not allowed to submit a tissue block or take punch biopsy cores from the paraffin block, the site may submit 15 unstained slides, but this is considered as an exception.  
10.2.3 A Pathology Report documenting that the submitted block, core, or slides contain tumor; the report must include the RTOG protocol number and patient's case number. The patient's name and/or other identifying information should be removed from the report. The surgical pathology numbers and information must NOT be removed from the report.  
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the submitted material is reviewed and is not tumor, the site may be assessed a protocol violation. The block, unstained, or punches must all be from the same block as the H&E being submitted.  
10.2.4 A Specimen Transmittal (ST) Form stating that the tissue is being submitted for Central Review.  
The Form must include the RTOG protocol number and the patient's case number.  
10.2.5 Central Review will be performed for every oropharyngeal case by Adel El-Naggar, MD, PhD.
institution # rtog foundation 3501
10.3 specimen collection for tissue

The following must be provided in order for the case to be evaluable for the Biospecimen Bank
(**Note**: For patients with oropharyngeal cancer, the H&E slides and block must be submitted for required central review as described above in Section 10.2 and would not be submitted again as described below.):
10.3.1 One H&E stained slide (slide can be a duplicate cut stained H&E; it does not have to be the diagnostic slide.)
10.3.2 A corresponding paraffin-embedded tissue block (the block must match the H&E being submitted) of the tumor or three 2 mm diameter core of tumor tissue, punched from the tissue block containing the tumor with a punch tool and embedded in paraffin along with a corresponding H&E slide. The new block made from the punches must be labeled with the surgical pathology number. **Note:** A kit with the punch, tube, and instructions can be obtained free of charge from the Biospecimen Bank. Block or core must be clearly labeled with the pathology identification number and block ID that corresponds to the Pathology Report. If sites are unable to submit tissue blocks, then an exception can be made to accept 15 unstained slides. The block, unstained, or punches must all be from the same block as the H&E being submitted (in Section 10.3.1).  
10.3.3 A Pathology Report documenting that the submitted block or core contains tumor. The report must include the RTOG protocol number and patient's case number. The patient's name and/or other identifying information should be removed from the report. The surgical pathology numbers and information must NOT be removed from the report.
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the submitted material is reviewed and is not tumor, the site may be assessed a protocol violation.  
10.3.4 Plasma and whole blood will be collected and stored for future translational studies. See Appendix IV for specimen processing and shipping information. Blood collection kits can be requested from the Biospecimen Bank free of charge at rtog@ucsf.edu or 415-476-7864.  
10.3.5 A Specimen Transmittal (ST) Form clearly stating that tissue/plasma/blood is being submitted for the Biospecimen Bank at UCSF; if for translational research, this should be stated on the form. The form must include the RTOG protocol number and patient's case number.  
The following materials must be provided to the Biospecimen Bank at UCSF with all specimens: A Specimen Transmittal (ST) Form documenting the date of collection of the biospecimen; the RTOG protocol number, the patient's case number, time point of study, and method of storage, for example, stored at -80 C, must be included.]
10.3.6 Storage Conditions Store frozen specimens at -80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not available:
Samples can be stored short term in a -20 C freezer (non-frost-free refrigerator preferred)
for up to 7 calendar days (please ship out Monday-Wednesday only; Canada: MondayTuesday).  
OR:
Samples can be stored in plenty of dry ice for up to 7 calendar days, replenishing daily
(ship out Monday-Wednesday only; Canada: Monday-Tuesday).  
OR:
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; Canada: Monday-Tuesday).  
Please indicate on ST Form the storage conditions used and time stored.  
10.3.7 Specimen Collection Summary (8/13/15)  
| Specimens for Central Review (mandatory for patients with oropharyngeal cancer)  and Tissue Banking (highly recommended)   |                                                                                                                                                     |                                                                                                                                                                                                                         |                                                                                 |
|----------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|
| Specimens taken from                                                                                                       | Collected when:                                                                                                                                     | Submitted as:                                                                                                                                                                                                           | Shipped:                                                                        |
| patient:                                                                                                                   |                                                                                                                                                     |                                                                                                                                                                                                                         |                                                                                 |
| Representative H&E stained                                                                                                 | Pre-treatment                                                                                                                                       | H&E stained slide                                                                                                                                                                                                       | Slide shipped ambient                                                           |
| slides of the primary tumor                                                                                                | Pre-treatment                                                                                                                                       |                                                                                                                                                                                                                         |                                                                                 |
| A corresponding paraffinembedded tissue block of the  primary tumor taken before  initiation of treatment or three 2 mm diameter cores of  tissue, punched from the  tissue block with a punch tool and embedded in paraffin with  4 unstained slides                                                                                                                            | Pre-treatment                                                                                                                                       | Paraffin-embedded tissue  block or block with 3 punch  biopsies with 4 unstained  slides Note: If site is not allowed  to send blocks or punches, then 15 unstained slides  will be allowed, but this is  an exception. | Block or punch block shipped ambient; include a cold pack  during warm weather. |
| Specimens for Banking and Translational Research (highly recommended)                                                      |                                                                                                                                                     |                                                                                                                                                                                                                         |                                                                                 |
| Specimens taken from                                                                                                       | Collected when:                                                                                                                                     | Submitted as:                                                                                                                                                                                                           | Shipped:                                                                        |
| patient: PLASMA: 5-10 mL of  anticoagulated whole blood in  EDTA tube #1 (purple/ lavender top) and centrifuge             | Pre-treatment, end of  radiation therapy (or within 2  weeks of end of radiation  therapy), and at 6 mos. from  the end of treatment.               | Frozen plasma samples  containing 0.5 mL per  aliquot in 1 mL cryovials  (five to eight)                                                                                                                                | Plasma sent frozen on dry  ice via overnight carrier                            |
| DNA: 5-10 mL of  anticoagulated whole blood in  EDTA tube #2 (purple/ lavender top) and mix                                | Pre-treatment (If site missed  this collection they can collect  this specimen at any time point or at follow up but this  must be noted on the ST) | Frozen whole blood  samples containing 1 ml  per aliquot in 1ml cryovials  (three to five)                                                                                                                              | Whole blood sent frozen on  dry ice via overnight carrier                       |
| 10.3.8                                                                                                                     | (8/13/15) Submit materials for Tissue Banking, Central Review, Translational Research as                                                            |                                                                                                                                                                                                                         |                                                                                 |  
10.3.8 **(8/13/15)** Submit materials for Tissue Banking, Central Review, Translational Research as follows: U. S. Postal Service Mailing Address: For Non-urgent, Non-frozen Specimens Only Biospecimen Bank at UCSF
University of California San Francisco Campus Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS): For Frozen Specimens and Urgent FFPE Samples Biospecimen Bank at UCSF 2340 Sutter Street, Room S341 (Box 1800) San Francisco, CA 94115
institution # rtog foundation 3501
questions 415-476-7864/fax 415-476-5271 rtog@ucsf.edu

10.4 Reimbursement The RTOG Foundation will reimburse institutions for submission of protocol-specified biospecimen materials sent to the Biospecimen Bank at UCSF. After confirmation from the Biospecimen Bank that appropriate materials have been received, ACR Clinical Trials Administration will authorize payment according to the schedule detailed in the study-specific contract.
institution # rtog foundation 3501
10.5 confidentiality/storage

(See the RTOG Patient Tissue Consent Frequently Asked Questions, http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx for further details.)
10.5.1 Upon receipt, the specimen is labeled with the RTOG protocol number and the patient's case number only. The Biospecimen Bank at USCF database only includes the following information: the number of specimens received, the date the specimens were received, documentation of material sent to a qualified investigator, type of material sent, and the date the specimens were sent to the investigator. No clinical information is kept in the database.  
10.5.2 Specimens for tissue banking will be stored for an indefinite period of time. Specimens for central review will be retained until the study is terminated. Specimens for the translational research component of this protocol will be retained until the study is terminated, unless the patient has consented to storage for future studies. If at any time the patient withdraws consent to store and use specimens, the material will be returned to the institution that submitted it.
institution # rtog foundation 3501
11.0 patient assessments 11.1 study

11.2 Details of Assessments (8/13/15)
11.2.1 It is necessary to repeat the ECHO or MUGA at week 12 (4 weeks post-completion of radiation therapy); see Section 7.7.2.  
11.2.2 A chest CT scan, or a PET/CT scan must be done within 42 calendar days prior to registration to rule out metastatic disease. In addition, a contrast enhanced CT scan or MRI or PET/CT
scan of the tumor site and neck nodes must be done within 42 calendar days prior to registration. Note: The CT scan of the neck and/or PET/CT performed for radiation planning may serve as both staging and planning tools.  
11.2.3 If the patient consents to submission of tissue and blood for translational research, primary tumor tissue will be submitted pre-treatment, and peripheral blood will be submitted pretreatment, at the end of radiation therapy, and at 6 months from end of treatment.  
11.2.4 Patients will be asked to document daily lapatinib/placebo on a pill diary during concurrent treatment and maintenance treatment, which will be collected by the institution as source documentation. Institutions will submit the DP form to RTOG at the end of concurrent treatment and every month during maintenance treatment (see Section 12.1).  
11.2.5 Evaluation During Radiotherapy A brief history and physical by a Radiation Oncologist and/or Medical Oncologist must be done weekly.  
Bilirubin and AST/ALT must be done 4 weeks after start of lapatinib/placebo.  
11.2.6 Evaluation in Follow Up Patients will be seen in long-term follow up every 3 months for years 1 and 2, every 6 months for years 3-5 and then annually until publication of study results.  
A brief history and physical by a Radiation Oncologist and/or Medical Oncologist and/or ENT or Head & Neck Surgeon must be done at 4 weeks and 3 months from the end of radiation treatment, then every 3 months through year 2, every 6 months for years 3-5, then annually. A laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is recommended at these time points but is not required.  
Post-radiation imaging evaluation of the primary tumor and neck at 3 months from the end of radiotherapy is required. The post-radiation imaging can be contrast enhanced CT, MRI, or PET/CT of the head and neck or "whole body" PET/CT (minimum neck and chest),
based on the preference of the treating clinician. However, if a pre-treatment PET/CT was performed, it is highly recommended that a post-radiation PET/CT be used as the postradiation imaging modality.  
Post-radiation imaging evaluation (CT scan or MRI) of the primary tumor and neck also must be done at 6 and 12 months from end of treatment, then annually until year 5.  
A chest CT scan must be done at 6 and 12 months from end of treatment, then annually until year 5.
institution # rtog foundation 3501
11.3 measurement of response/progression 11.3.1

Response and confirmation of local (primary site) or regional (neck) "tumor clearance" are not endpoints in this study. Clinical or radiographic evidence of progressive local-regional disease beyond 20 weeks should be documented in the clinical record and ideally confirmed by local or regional biopsy, neck dissection, or salvage surgery. CT or MRI (of head and neck region, with Chest CT), or PET/CT (including chest anatomy) may be used as radiographic evaluation of overall cancer status. The primary, neck and chest portions of the scans should be evaluated and reported separately. The CT portion of a PET/CT may serve as sufficient radiographic evaluation of the chest. If CT or MRI is used for evaluation of the head and neck region, CT of chest will be needed to rule out distant disease or second primaries at the designated evaluation intervals as outlined above in Section 11.2.6 and Appendix I.  
11.3.2 Local or Regional Progression Local (primary site) or regional (neck) progression is defined as palpable residual disease or CT/MRI evidence of persistent disease at the primary site or neck. The location of progressive disease should be separately distinguished (local vs. neck) to document the precise pattern of failure if possible. Progression of local or regional disease should be confirmed by biopsy when possible but may be clinically assessed and documented in the clinical record at the judgment of the treating clinicians.  
11.3.3 Distant Metastasis Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended where possible. A solitary, spiculated lung mass/nodule is considered a second primary neoplasm unless proven otherwise.  
11.3.4 Second Primary Neoplasm Tumor reappearing with the initial and immediate adjoining anatomical region of the primary will be considered local recurrence. Multiple lung nodules/masses are considered distant metastases from the index cancer unless proven otherwise.  
11.4 Criteria for Discontinuation of Protocol Treatment Progression of disease; Unacceptable adverse events per the judgment of the treating physician(s); Patient refusal.
If protocol treatment is discontinued, follow up and data collection will continue as specified in the protocol.
institution # rtog foundation 3501
11.5 quality of life/patient-reported outcomes

study, such as quality of life assessment. If the patient consents to participate in the quality of life
(QOL) component of the study, sites are required to administer the baseline QOL and PRO assessments prior to the start of protocol treatment: the PSS-HN, FACT-HN, and XeQOLS. Outcomes will be assessed at baseline (pretreatment) and at 3, 12, and 24 months from completion of radiation treatment.  
11.5.1 *The Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N)* is a multidimensional, patient-self report quality of life (QOL) instrument specifically designed and validated for use with head and neck patients. The patient can complete the 12-item head and neck subscale in 5-10 minutes. The site research nurse or CRA is encouraged to be sensitive to each patient's demeanor. If patients appear particularly uncomfortable answering a question, they will be informed that they can skip that question. Similarly, interviewers will give patients a short break if the patient appears fatigued or otherwise in need of a few minutes break.  
11.5.2 *The University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS)* consists of 15 items covering 4 major domains of oral health-related quality of life: physical functioning, personal/psychological functioning, social functioning, and pain/discomfort issues. The patient can respond to the 15 items in the scale in approximately 5 minutes. The Scale is only available in English.  
11.5.3 *The Performance Status Scale for Head and Neck Cancer (PSS-HN)* consists of assessment of 3 functional areas (subscales): Normalcy of Diet, Eating in Public, and Understandability of Speech. The site research nurse or clinical research associate (CRA) will administer the PSSHN. Interviewers are encouraged to be sensitive to each patient's demeanor. If patients appear particularly uncomfortable answering a question, they will be informed that they can skip that question. Similarly, interviewers will give patients a short break if the patient appears fatigued or otherwise in need of a few minutes break. The interviewer rates the patient on each scale based on the patient's responses to targeted questions. The PSS-HN takes approximately 5 minutes to complete.
institution # rtog foundation 3501
12.0 data collection (9/27/16) data

Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be used (first-last). Last names with apostrophes will be identified by the first letter of the last name.  
Within 14 calendar days of study entry
institution # rtog foundation 3501
12.1 summary of data submission

Item Due Demographic Form **(A5)** Initial Evaluation Form **(I1)** Pathology Report **(P1)** Slides/Blocks **(P2)** PSS-HN **(QP)** FACT-HN **(FA)** Xe-QOL **(L4)**  
| Surgery Form (S1) Surgical Operative Report (S2) Surgical Pathology Report (S5)   |
|-----------------------------------------------------------------------------------|  
Radiotherapy Form **(T1)** Daily Treatment Record **(T5)**  
Within 7 calendar days of RT end  
PSS-HN **(QP)** FACT-HN **(FA)** Xe-QOL **(L4)**
Treatment Form **(TF)** Within 7 calendar days of end of treatment Pill Diary **(DP)** End of concurrent treatment and every 30 calendar days during maintenance treatment Only for patients who have surgery to the primary site and/or to regional nodes post-treatment At 3, 12, and 24 months from end of RT
Follow-up Form **(F1)** q3 mos. for years 1-2, q6 mos. for years 3-5, then annually until publication of study results
institution # rtog foundation 3501
12.2 summary of dosimetry digital

Item Due Preliminary Dosimetry Information **(DD)**
Digital Data Submission - Treatment Plan submitted in DICOM format to RTOG via TRIAD exported from treatment planning machine by Physicist Within 7 calendar days of start of RT  
Digital data submission includes the following:
DICOM CT data (non-contrast CT and CT with contrast; see Section 6.3.2)
DICOM STRUCTURE DICOM RT PLAN DICOM DOSE
NOTE: Sites must notify RTOG via e-mail RTOGRTQA@acr.org **after digital data is submitted. The**
e-mail must include both the study, "Foundation 3501", **and case numbers.**
Digital Data Submission Form (DT) - Web data entered (form is located on RTOG website: Foundation 3501 under Forms).  
Final Dosimetry Information Within 7 calendar days of RT end Radiotherapy Form **(T1)** Daily Treatment Record **(T5)**
Modified digital patient data as required by RTOG will be submitted via TRIAD
12.2.1 Digital Data Submission to RTOG Headquarters Digital data will be submitted to RTOG via the site's TRIAD account.  
12.2.2 Method of Plan Submission RTOG will provide sites with the American College of Radiology Imaging Network's image acquisition and management software, TRIAD, via electronic installation. TRIAD offers a webbased, software solution allowing institutions to submit DICOM data securely through electronic transmission. Internal to the site, TRIAD allows the site to "DICOM push" from the site's Treatment Planning System (TPS), thus eliminating the need to burn physical media. Once the institution has transferred the RT data onto a TRIAD workstation, the software will anonymize, encrypt, and submit the DICOM RT data via secure internet to the RTOG image archive. For more information please visit the TRIAD web site at https://triad.acr.org.  
Institutions initiate installation of TRIAD by e-mailing the name and e-mail address of the person(s) responsible at the site for submitting RT data for the trial (recommend the Physicist and/or Dosimetrist) to TRIAD-Support@acr.org. The site will then receive a TRIAD greeting letter, which describes how to prepare for the installation.  
TRIAD technical assistance may be requested by e-mailing TRIAD-Support@acr.org.  
Please always include the institution name and trial number when requesting TRIAD technical assistance.
institution # rtog foundation 3501
13.0 statistical considerations 13.1 primary

Patients will be randomized to 1 of 2 treatment arms. Additionally, patients will be stratified according to age (≤ 65 vs. > 65); T stage (T1-3 vs. T4); and N stage (N0-2a vs. N2b-3).  
13.4 Definitions of Failure The following table shows how each first event will be counted for progression-free survival, localregional failure, and distant metastasis. Anything not explicitly in the table (e.g., second primary tumor) is not considered an event, and the patient will continue to be followed for failure. For overall survival, death from any cause will be considered a failure. All failure times will be measured from randomization to the date of failure, competing risk, or last follow-up.  
13.5 Sample Size and Patient Accrual (9/27/16)
This study will be a randomized phase II screening trial as proposed by Rubinstein, et al (2005).  
Based on the accrual to RTOG 0129 in this population, it is expected that the monthly accrual will be 12 patients after the first 6 months post-activation (allowing for IRB approvals). In RTOG 0129, this group of patients treated on the accelerated fractionation arm had a 2-year progression-free survival (PFS) rate of 53.5%. Hazard rates for first and second years are 37% and 15%. Based on discussions with the study chair, a 35% reduction in the hazard rate is clinically meaningful. With statistical power 0.80 and significance level 0.20 (1-sided) and one interim efficacy and futility analysis, the Lan-Demets (OF) spending function boundary for efficacy and rho family spending function with parameter of 1.5 for futility were utilized to derive a nonbinding rule. A total of 69 PFS events are required. To observe the required number of events, a sample size of 158 accrued over 1.22 years with an additional 2.6 years of follow-up (total study duration 4.3 years including 6 months for IRB approvals) is required. Allowing for up to 10% of patients to be ineligible or not evaluable, **the total original required sample size is 176**.  
| ProgressionFree Survival                                                                                 | Local-Regional   |                |                |
|---------------------------------------------------------------------------------|------------------|----------------|----------------|
| First event                                                                     | Failure          |                |                |
| None                                                                            | Censored         | Censored       | Censored       |
| Local-regional progression or recurrence                                        | Failure          | Failure        | Competing risk |
| Distant metastasis                                                              | Failure          | Competing risk | Failure        |
| Death due to study cancer or from  unknown causes                               | Failure          | Failure        | Competing risk |
| Death to due any other reason                                                   | Failure          | Competing risk | Competing risk |
| Salvage surgery of primary with tumor  present/unknown                          | Failure          | Failure        | Competing risk |
| Salvage neck dissection with tumor  present/unknown, > 20 weeks from end  of RT | Failure          | Failure        | Competing risk |  
Following activation of the study little accrual is anticipated initially. The date at which the first patient is accrued will be used as the baseline for monitoring accrual. If the total accrual during months 18 through 24 is less than 20% of the projected total for 6 months of accrual (15 patients),
then the study statistician will recommend to the RTOG DMC and the sponsor that the protocol will be discontinued. If the total accrual is between 21-49%, then the protocol will continue to accrue subjects pending approval to remain open by the RTOG DMC and the study sponsor.
institution # rtog foundation 3501
revised sample size and patient

13.2.1 Overall survival; 13.2.2 Distant metastasis; 13.2.3 Adverse events; 13.2.4 Compliance with planned treatment; 13.2.5 Local-regional control; 13.2.6 Quality of life and patient-reported outcomes;  
13.2.7 HER2 expression, amplification and heterodimerization, EGFR ligand expression, EGFR  
polymorphisms, hypoxia, and EMT characteristics as biomarkers of lapatinib response, sensitivity, and resistance, PFS, and metastasis.  
As of September 2016, the observed accrual rate in this study is about 30 patients/year (2.5/month). To finish accrual within a reasonable timeframe and to maintain the same design parameters detailed above, we plan to accrue a total of 142 patients (128 analyzable), with a total accrual duration of 4.7 years instead of 5.9 years. According to this plan, we will finish accrual around March 2017.  
13.6 Analysis Plan (9/27/16)
Progression-free and overall survival rates will be estimated using the Kaplan-Meier method (1958) and rates of distant metastasis (DM) and local-regional control (LRC) by the cumulative incidence method (Kalbfleisch 1980) to account for competing risks (see Section 13.4). The distributions of the progression-free and overall survival times will be compared between treatment arms with a one sided log rank test (Mantel, 1966). Distant metastasis and localregional control will be compared using cause-specific log rank test. If the resulting p-value for PFS is < 0.1803, the result will be interpreted as a significant indication of lapatinib improving progression-free survival of these patients to warrant a definitive phase III trial. Only adverse events (AEs) assessed to be definitely, probably, or possibly related (if the relationship is missing, it will be assumed to be definitely, probably, or possibly) to protocol treatment will be considered. The rates of adverse events and treatment compliance will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test.  
Comparison of change from baseline quality of life scores between the 2 arms will be done using a 2-sample independent t test. With 158 patients, we will have 87% power to detect an effect size of 0.5 with a two-sided type I error rate of 5% and the statistical power will be 79% and 66% to detect effect sizes of 0.5 with 126 and 94 patients. Analysis of the covariance model (ANCOVA) will be used to adjust for effects from other factors.  
For analysis of local-regional control, distant metastasis, PFS, and OS, we will examine whether patients with normal baseline levels of biomarkers have a different prognosis than patients with abnormal baseline levels by calculating the product-limit estimates of the survival function and comparing those estimates using the log-rank statistic. The relationship between local-regional control, distant metastasis, PFS, OS, and abnormal baseline marker levels also will be explored by fitting Cox proportional hazards regression models, both adjusted for baseline disease and patient characteristics and unadjusted. Assuming usable baseline tissue/blood samples can be obtained from 118 eligible patients (~75%), this will provide at least modest power (>69%) to detect large differences (hazard ratios > 2.0) between patients with normal and abnormal marker levels, assuming 50% abnormal prevalence, with a two-sided 5% alpha, for the PFS endpoint.  
13.6.1 Interim Analysis to Monitor Study Progress Interim reports will be prepared twice each year until the final analysis has been accepted for presentation or publication. In general, 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 AEs. The RTOG Data Monitoring Committee (DMC) will review this study twice a year in conjunction with the RTOG
semiannual meetings with respect to patient accrual and morbidity. The DMC also will review this study on an "as needed" basis between meetings.  
13.6.2 Significance Testing for Early Termination and Reporting One interim treatment comparison will be performed when 50% (34 PFS failures) of the 69 required number of PFS failures are observed. Only the primary endpoint will be tested in the interim analysis. The efficacy will be tested using boundary of 0.0699 on the p value scale for the interim tests and 0.1803 for the final analysis to preserve an overall alpha level of 0.20 for the study. A single interim futility analysis will be conducted when one-half (34) of the requisite events for definitive analysis have been observed. If the p value is equal to or greater than 0.5827 favoring the control (i.e. in the wrong direction with respect to demonstrating that the lapatinib arm is more favorable), then early stopping will be considered. The results will be reported to the RTOG DMC with the treatment blinded. The responsible statistician may recommend early reporting of the results and/or stopping accrual (if applicable) of the trial if the treatment effect with respect to PFS is highly significant or if it is not likely to be.  
13.6.3 Analysis for Reporting the Initial Treatment Results The analysis to report the initial results of treatment will be undertaken when each patient has finished concurrent therapy, around July 2017. All randomized patients (ITT) will be included in the analysis. Eligible patients with both on-study and follow-up information will be considered for sensitivity analysis. The emphasis of this analysis will be on treatment compliance and adverse events. The usual components of this analysis are:
Tabulation of all cases entered, and any excluded from analysis with reasons for exclusion; Patient accrual rate; Institutional accrual; Distribution of important baseline prognostic variables; Frequency and severity of adverse events; Compliance rate for treatment delivery with respect to the protocol prescription; Observed results with respect to the endpoints described above.  
Only adverse events (AEs) assessed to be definitely, probably, or possibly related (if the relationship is missing, it will be assumed to be definitely, probably, or possibly) to protocol treatment will be considered. The rates of adverse events, treatment compliance, will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test.  
13.6.4 Analysis for Reporting the Final Treatment Results The analysis to report the definitive results of treatment will be undertaken when 69 events (total from both arms) have been reported for the primary endpoint, PFS, unless the criteria for early stopping are met. The time from when accrual is finished to this analysis is projected to be approximately 2.7 years based on the observed accrual rate. All randomized patients (ITT) will be included in this analysis. Eligible patients with both on- study and follow-up information will be considered for sensitivity analysis. The usual components of this analysis are:
Tabulation of all cases entered, and any excluded from analysis with reasons for exclusion; Patient accrual rate; Institutional accrual; Distribution of important baseline prognostic variables; Frequency and severity of adverse events; Observed results with respect to the endpoints described above.  
The difference in PFS between the control arm and the experimental arm will be tested using the one sided log-rank statistic at the significance level of 0.1803 given that the one interim analysis is carried out and shows no statistical significance. If the resulting p-value for efficacy is <0.1803, this result will be interpreted as an indication of lapatinib in improving progressionfree survival in these patients.  
A final analysis report will be prepared and provided for review by the co-investigators. Results for dissemination will be developed, and a manuscript drafted for review, approval, and submission. After manuscript acceptance, patient follow up will be discontinued and the trial terminated. It is anticipated that termination will occur approximately 3.9 years from when the accrual is finished. This time-frame may be extended depending on factors such as the observed accrual and event rates, in which case a new trial termination date will be established.
institution # rtog foundation 3501
references

Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. *J Clin Oncol.* 21: 92-98, 2003. Alroy I, Arden Y. Biochemistry of HER-2 oncogenesis in breast cancer. *Breast Disease*. 11: 31-48, 2000 Al-Sarraf M, LeBlance M, Shanker PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized intergroup study 0099. *J Clin Oncol*. 16: 1310-1317, 1998.  
Amador ML. An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. *Cancer Res*. 64(24)9139-43, 2004. American Cancer Society. Cancer Facts and Figures. 2010.  
American Cancer Society. Caring for the patient with cancer at home: Diarrhea.  
http://www.cancer.org/Treatment/TreatmentsandSideEffects/PhysicalSideEffects/DealingwithSymptomsatHom e/caring-for-the-patient-with-cancer-at-home-diarrhea Ang KK, Berkey BA, Tu, X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. *Cancer Res*. 62(24): 7350-6, 2002.  
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. NEJM. 363(1): 24-35, 2010. [Epub 2010 Jun 7] Ang KK. A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas. 2011 ASCO Annual Meeting. Abstract 5500.  
Arteaga CL. ErbB-targeted therapeutic approaches in human cancer. *Exp Cell Res*. 284(1): 122-30, 2003.  
Atalay G, Cardoso F, Awada A, et al. Novel therapeutic strategies targeting the EGFR family and it's downstream effectors in breast cancer. *Ann Oncol*. 14: 1346-1363, 2003. Beckhardt RN. HER-2/neu oncogene characterization in head and neck squamous cell carcinoma. Arch Otolaryngol HN Surg. 121(11): 1265-70, 1995.  
Benson A, Jaffer AA, Catalano RB, et al. Recommended Guidelines for the Treatment of Cancer TreatmentInducted Diarrhea. J Clin Oncol. 22: 2918-2926, 2004.  
Bjordal K, de Graeff A, Fayers PM, et al. A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC Quality of Life Group. *Eur J Cancer*. 36(14): 1796-807, 2000.  
Bova RJ, Quinn DI, Nankervis JS, et al. Cyclin D1 and p16INK4a expression predict reduced survival in carcinoma of the anterior tongue. *Clin Cancer Res*. 5: 2810–9,1999.  
Cavalot A. Prognostic impact of HER-2/neu expression on squamous head and neck carcinomas *Head &*
Neck. 29(7): 655-64, 2007. Cella DF, et al., The Functional Assessment of Cancer Therapy scale: Development and validation of chemoradiotherapy regimens. *Amer Soc of Clin Onc*. 412, 2000. Charma R, Tobin P, Clarke SJ. Management of chemotherapy-induced nausea, vomiting, oral mucositis, and diarrhea. Lancet/Oncology. 6: 93-102, 2005.
institution # rtog foundation 3501
references (continued)

Chung C. GLI family zinc finger 1 expression and metastasis in patients with head and neck squamous cell carcinoma treated with radiation therapy (RTOG 90-03). *J Clin Oncol*. In press.  
Chung CH, Zhang Q, Hammond EM, et al. Integrating epidermal growth factor receptor assay with clinical parameters improves risk classification for relapse and survival in head-and-neck squamous cell carcinoma.  
IJROBP. [Epub 2010 Aug 21 ahead of print] Cox DR. Regression models and life tables. *J Royal Stat Soc* (series B). 34:187-229, 1972.  
Craven JM. Expression of c-erbB-2 gene in human head and neck carcinoma *Anticancer Res*. 12(6B): 2273-6, 1992.  
Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. *J Clin Oncol*. 22(1): 69-76, 2004. [Epub 2003 Dec 2] Diermeier S. Epidermal growth factor receptor coexpression modulates susceptibility to Herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation. *Exp Cell* Res. 304(2): 604-19, 2005.  
Dijkema T, Raaijmakers CP, Ten haken RK, et al. Parotid gland function after radiotherapy: The combined Michigan and Utrecht experience. *IJROBP*. [Epub ahead of press 2010]. Field JK. C-erbB-2 expression in squamous cell carcinoma of the head and neck. *Anticancer Res*. 12(3): 6139, 1992.  
Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. *NEJM*. 349: 2091-2098, 2003. Frederick BA. Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. *Mol Cancer Ther*. 6(6):1683-91, 2007.  
Fu KK, Pajak TF, Trotti A, et al. A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. *IJROBP*. 48: 7-16, 2000. Gregoire V, Eisburch A, Hamoir M, and Levendag P. Proposal for the delineation of the nodal CTV in the node-negative and the post-operative neck. *Radiotherapy and Oncology*. 79:15-20, 2006.  
Gruttgen A, Reichenzeller M, Junger M, et al. Detailed gene expression analysis but not microsatellite marker analysis of 9p21 reveals differential defects in the INK4a gene locus in the majority of head and neck cancers. J Pathol. 194:311-7, 2001.  
Harrington K. et al. Phase II study of oral Lapatinib, a dual-tyrosine kinase inhibitor, combined with chemoradiotherapy (CRT) in patients with advanced squamous cell carcinoma of the head and neck
(SCCHN). *J Clin Oncol*. 28:15s, 2010 suppl. Abstract 5505. GSK study 884.  
Hatakeyama H. Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximabresistance in head and neck squamous cell carcinoma. *PLoS ONE*. 5(9):e12702, 2010.  
Hendriks BS, Opreskolk, Wiley HS, Lauffenburger,D .Quantitative analysis of HER-2-mediated effects on HER2 and EGFR Endocytosis. *J of Biol Chem.* 278 (26): 23343-23351, 2003. Henson 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*. 37(1): 84-93, 2001.  
Hou L. Oral cancer progression and c-erbB-2/neu proto-oncogene expression. *Cancer Letter*. 65(3): 215-20, 1992.  
Ibrahim SO. Expression of c-erbB proto-oncogene family members in squamous cell carcinoma of the head and neck. *Anticancer Res*. 17(6D): 4539-46, 1997. Kalbfleisch JD, Prentice RL. *The Statistical Analysis of Failure Time Data*. New York: Wiley; 1980. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat Assoc. 53: 457-481, 1958.  
Karvonen-Gutierrez CA, Ronis DL, Fowler KE, et al. Quality of life scores predict survival among patients with head and neck cancer. *J Clin Oncol*. 26(16): 2754-60, 2008. Kearsley JH. A comparison of epidermal growth factor receptor (EGFR) and c-erbB-2 oncogene expression in head and neck squamous cell carcinomas. *Pathology*. 23(3): 189-94, 1991.  
Khambata-Ford S. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. *J Clin Oncol*. 25(22): 3230-7, 2007.  
Khan AJ, King BL, Smith BD, et al. Characterization of the HER-2/neu oncogene by immunohistochemical and fluorescence in situ hybridization analysis in oral and oropharyngeal squamous cell carcinoma. Clin Cancer Res. 8:540-8, 2002. Le QT. Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: Radiation Therapy Oncology Group trial 90-03. JCO. 27(26): 4281-6, 2009.  
List MA, D'Antonio LL, Cella DF, et al. The performance status scale for head and neck cancer patients and the functional assessment of cancer therapy-head and neck scale: A study of utility and validity. *Cancer*. 77: 2294-301, 1996.  
List MA, Siston A, Haraf D, et al. Quality of life and performance in advanced head and neck cancer (HNC: Comparison between paclitaxel-based (P-CT/XRT) and cisplatin-based (C-CT/XRT) concomitant chemoradiotherapy: A prospective examination. *J Clin Oncol*. 17: 1020-8, 1999.  
List MA, Stracks J. Evaluation of quality of life in patients definitively treated for squamous carcinoma of the head and neck. *Curr Opin Oncol*. 12(3):215-20, 2000.  
Logemann JA, Pauloski BR, Rademaker AW, et al. Swallowing disorders in the first year post-radiation and chemoradiation. Head & Neck. 30: 148-158, 2008. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemotherapy Reports. 5: 163-170, 1966.  
Martello G. A MicroRNA targeting dicer for metastasis control. *Cell*. 141:1195-1207, 2010.  
Martino R, Ringash J. Evaluation of quality of life and organ function in head and neck squamous cell carcinoma. *Hematol Oncol Clin North Am*. 22(6):1239-56, 2008. Review.  
Motoyama AB. The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. *Cancer Res*. 62(11): 3151-8, 2002.  
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 Reviews Oncol/Hemat*. 62:251–267, 2007.  
Nahta R, Esteva FJ. HER-2 targeted therapy: Lessons learned and future directions. *Clin Canc Res*. 9 (14): 5078-5084, 2003.  
National Cancer Institute. Overview of nutrition in cancer care (PDQ®). http://www.cancer.gov/cancertopics/pdq/supportivecare/nutrition Nguyen NP, Frank C, Moltz CC, et al. Impact of dysphagia on quality of life after treatment of head and neck cancer. *IJROBP*. 61:772–8, 2005.  
Pignon JP, le Maître A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomized trials and 17,346 patients. MACH-NC Collaborative Group.  
Radiother Oncol. 92(1): 4-14, 2009. [Epub 2009 May 14] Rait AS, Pirollo KF, Ulick D, et al. HER-2-targeted antisense oligonucleotide results in sensitization of head and neck cancer cells to chemotherapeutic agents. *Ann N Y Acad Sci*. 1002:78-89, 2003. Rampias T, Sasaki C, Weinberger P, Psyrri A. E6 and E7 gene silencing and transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells. *J Natl Cancer Inst*. 101:412-23, 2009. Reed AL, Califano J, Cairns P, et al. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. *Cancer Res*. 1996;56:3630–3.  
Ringash J, Bezjak A, O'Sullivan B, Redelmeier DA. Interpreting differences in quality of life: The FACT-H&N in laryngeal cancer patients. *Qual Life Res*. 13(4): 725-33, 2004. Ringash J, Warde P, Lockwood G, O'Sullivan B, Waldron J, Cummings B.Postradiotherapy quality of life for head-and-neck cancer patients is independent of xerostomia. *IJROBP*. 61(5): 1403-7, 2005.  
Ringash J, O'Sullivan B, Bezjak A, Redelmeier DA. Interpreting clinically significant changes in patientreported outcomes. *Cancer.* 110(1):196-202, 2007.  
Ringash J, Lockwood G, O'Sullivan B, et al. Hyperfractionated, accelerated radiotherapy for locally advanced head and neck cancer: quality of life in a prospective phase I/II trial. *Radiother Oncol*. 87(2):181-7, 2008. Epub 2008 Jan 22. Rogers SN, Johnson IA, Lowe D. Xerostomia after treatment for oral and oropharyngeal cancer using the University of Washington saliva domain and a Xerostomia-Related Quality-of-Life Scale. *IJROBP*. 77(1): 1623, 2010. [Epub 2009 Aug 11]
Rubin Grandis J. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival *JNCI.* 90(11): 799-801, 1998. Rubinstein LV, Korn EL, Freidlin B, et al. Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol. 23: 28, 7199-7206, 2005.  
Rusnak DW, Lackey K, Afflek K, et al. The effects of the novel reversible, EGFR/ErbB2 tyrosine kinase inhibitor, GW 572016, on the growth of human normal and tumor derived cell lines in vitro and in vivo. Mol Canc Therapeutics. 1: 85-94, 2001 Saltz LB. Understanding and Managing Chemotherapy-Induced Diarrhea. *J Support Oncol*.1:35-46, 2003. Siddiqui F, Pajak TF, Watkins-Bruner D et al. Pretreatment quality of life predicts for locoregional control in head and neck cancer patients: a radiation therapy oncology group analysis. *IJROBP*. 70(2): 353-60, 2008.  
Söderberg O. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods. 3(12): 995-1000, 2006. Epub 2006 Oct 29.  
Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? *Cancer*. 110(7): 1429-35, 2007. Webster GJ, Rowbottom CG, Ho KF, et al. Evaluation of larynx-sparing techniques with IMRT when treating the head and neck. *IJROBP*. 72:617-22, 2008.  
Weibrecht I, Leuchowius KJ, Clausson CM, et al. Proximity ligation assays: A recent addition to the proteomics toolbox. *Expert Rev Proteomics*. 7(3): 401-9, 2010. Review. Weymuller EA, Yueh B, Deleyiannis FW, et al. Quality of life in patients with head and neck cancer: Lessons learned from 549 prospectively evaluated patients. *Arch Otolaryngol Head Neck Surg*. 126(3): 329-35; discussion 335-6, 2000. Xia W, Lau YK, Zhang HZ, et al. Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. *Clin Cancer Res*. 5:4164-74, 1999.  
Xia W, Mullin RJ, Keith BR et al. Anti-tumor activity of GW 572016: A dual tyrosine kinase inhibitor blocks EGF activation of EGFR/ErbB2 and downstream Erk 1 / 2 and AKT pathways. *Oncogene.* 21: 6255-6263, 2002. Yarden Y. Biology of HER2 and its importance in breast cancer. *Oncology*. 61 (Suppl 2), 1-13, 2001.  
Zhang W. Epidermal growth factor receptor gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation. *Clin Can Res*. 11:600-5, 2005. Zhou Y, Brattain, MG. A novel strategy of colon cancer therapy: Targeting both EGFR and ErbB2 receptors. Proceedings AACR: 44, Abstract 5529, 2003.  
| (8/13/15) APPENDIX I: STUDY PARAMETER TABLE: *See Section 11.2 for details and exceptions   |                                          |                                               |                                                            |                        |                        |    |    |    |
|---------------------------------------------------------------------------------------------|------------------------------------------|-----------------------------------------------|------------------------------------------------------------|------------------------|------------------------|----|----|----|
| Assessments                                                                                 | Prior to  Registration  (calendar  days) | Prior to Treatment                            | q7 days                                                    |                        |                        |    |    |    |
| (calendar days)                                                                             | During  Treatment                        | From End of Radiation Therapy (calendar days) | q 3 mos. in year  2; 6 mos. in  years 3-5; then  annually* |                        |                        |    |    |    |
| 4                                                                                           | 3                                        | 6                                             | 9 mos.                                                     | 12                     |                        |    |    |    |
| weeks                                                                                       | mos.                                     | mos.                                          | mos.                                                       |                        |                        |    |    |    |
| Complete history/physical                                                                   | 28 days                                  | Brief H&P                                     | X*                                                         | X*                     | X*                     | X* | X* | X* |
| Rad Oncology Exam                                                                           | X*                                       | X*                                            | X*                                                         | X*                     | X*                     |    |    |    |
| Med Oncology Exam                                                                           | 28 days                                  | X*                                            | X*                                                         | X*                     | X*                     | X* |    |    |
| Zubrod                                                                                      | 14 days                                  | X                                             | X                                                          | X                      | X                      | X  | X  |    |
| Weight                                                                                      | 28 days                                  | X                                             | X                                                          | X                      | X                      | X  | X  |    |
| Chest CT or PET/CT                                                                          | 42 days                                  | X*                                            | X*                                                         | Annually until  year 5 |                        |    |    |    |
| Contrast enhanced CT or MRI or  PET/CT of tumor site and neck  nodes                        | 42 days                                  | X*                                            | X*                                                         | X*                     | Annually until  year 5 |    |    |    |
| EKG                                                                                         | 84 days                                  |                                               |                                                            |                        |                        |    |    |    |
| ECHO or MUGA                                                                                | 84 days                                  | X*                                            |                                                            |                        |                        |    |    |    |
| ENT or H&N Surgeon exam                                                                     | 42 days                                  | See Sec.                                      | See Section 11.2.6                                         |                        |                        |    |    |    |
| 11.2.5                                                                                      |                                          |                                               |                                                            |                        |                        |    |    |    |
| CBC, Diff, Platelets                                                                        | 14 days                                  | X                                             | X                                                          | X                      | X                      | X  |    |    |
| Na, K, glucose, Ca, Mg                                                                      | 14 days                                  |                                               |                                                            |                        |                        |    |    |    |
| Na, K, Cl, glucose, Ca, Mg,                                                                 | X                                        | X                                             | X                                                          | X                      | X                      | X  |    |    |
| albumin Bilirubin, AST/ALT                                                                  | 14 days                                  | See Sec. 11.2.5                               | X                                                          | X                      | X                      | X  |    |    |
| Serum creatinine or creatinine                                                              | 14 days                                  | X                                             | X                                                          | X                      | X                      | X  |    |    |
| clearance Serum pregnancy test, for                                                         | 14 days                                  |                                               |                                                            |                        |                        |    |    |    |
| women of childbearing potential Adverse Event Eval, including                               | X                                        | X                                             | X                                                          | X                      | X                      | X  | X  |    |
| mucosal assessment Dental assessment                                                        | Recommended at 84 days                   |                                               |                                                            |                        |                        |    |    |    |
| Whole body PET scan                                                                         | Recommended at 42 days                   |                                               |                                                            |                        |                        |    |    |    |
| Audiogram                                                                                   | Recommended at 84 days                   |                                               |                                                            |                        |                        |    |    |    |
| Swallowing assessment                                                                       | Recommended at 28 days                   |                                               |                                                            |                        |                        |    |    |    |
| Nutritional eval for PEG tube                                                               | Recommended prior to tx                  |                                               |                                                            |                        |                        |    |    |    |
| *Pill Diary                                                                                 | End of tx                                | q30  days.  for 3  mos.                       |                                                            |                        |                        |    |    |    |
| QOL/PRO assessments, if                                                                     | X                                        | X                                             | X                                                          | at 24 mos. from        |                        |    |    |    |
| patient consents                                                                            | end of tx                                |                                               |                                                            |                        |                        |    |    |    |
| Tissue/blood for research, if                                                               | End of                                   | X                                             |                                                            |                        |                        |    |    |    |
| patient consents                                                                            | Prior to treatment                       | RT                                            |                                                            |                        |                        |    |    |    |
institution # rtog foundation 3501
appendix ii zubrod performance scale

0 Fully active, able to carry on all predisease activities without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry work of a light or sedentary nature. For example, light housework, office work  
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3 Capable of only limited self-care, confined to bed or chair 50% or more of waking hours 4 Completely disabled. Cannot carry on self-care. Totally confined to bed 5 **Death**  
| Class   | Functional Capacity                                                                                                                                                                                                                                           | Objective Assessment                                              |
|---------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|
| I       | Patients with cardiac disease but without resulting limitations of  physical activity. Ordinary physical activity does not cause undue  fatigue, palpitation, dyspnea, or anginal pain.                                                                       | No objective evidence of  cardiovascular disease.                 |
| II      | Patients with cardiac disease resulting in slight limitation of physical  activity. They are comfortable at rest. Ordinary physical activity  results in fatigue, palpitation, dyspnea, or anginal pain.                                                      | Objective evidence of  minimal cardiovascular  disease.           |
| III     | Patients with cardiac disease resulting in marked limitation of  physical activity. They are comfortable at rest. Less than ordinary  activity causes fatigue, palpitation, dyspnea, or anginal pain.                                                         | Objective evidence of  moderately severe  cardiovascular disease. |
| IV      | Patients with cardiac disease resulting in inability to carry on any  physical activity without discomfort. Symptoms of heart failure or  the anginal syndrome may be present even at rest. If any physical  activity is undertaken, discomfort is increased. | Objective evidence of  severe cardiovascular  disease.            |
appendix iii
appendix ii zubrod performance scale

AJCC STAGING SYSTEM
Edge, SB, ed. *AJCC Cancer Staging Manual*. 7th ed. New York, NY: Springer; 2010.
appendix iii
head & neck staging-primary tumor

TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma *in situ*
appendix iii
lip and oral cavity

| TX                                                                                                                     | Primary tumor cannot be assessed                                                                                                                                                                                                                                                                                                                                                                          |
|------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| T0                                                                                                                     | No evidence of primary tumor                                                                                                                                                                                                                                                                                                                                                                              |
| Tis                                                                                                                    | Carcinoma in situ                                                                                                                                                                                                                                                                                                                                                                                         |
| T1                                                                                                                     | Tumor 2 cm or less in greatest dimension                                                                                                                                                                                                                                                                                                                                                                  |
| T2                                                                                                                     | Tumor more than 2 cm but not more than 4 cm in greatest dimension                                                                                                                                                                                                                                                                                                                                         |
| T3                                                                                                                     | Tumor more than 4 cm in greatest dimension                                                                                                                                                                                                                                                                                                                                                                |
| T4a                                                                                                                    | Moderately advanced local disease* (lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of  face (i.e., chin or nose) (oral cavity) Tumor invades adjacent structures only (e.g., through cortical bone [mandible or  maxilla] into deep [extrinsic] muscle of tongue [genioglossus, hyoglossus, palatoglossus, and  styloglossus], maxillary sinus, skin of face) |
| T4b                                                                                                                    | Very advanced disease Tumor invades masticator space, pterygoid plates or skull base and/or encases internal  carotid artery                                                                                                                                                                                                                                                                              |
| *Note: Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumor as T4. |                                                                                                                                                                                                                                                                                                                                                                                                           |
appendix iii
nasal cavity and paranasal sinuses

| Maxillary Sinus T1                                                                                                                                                                                | Tumor limited to maxillary sinus mucosa with no erosion or destruction of bone                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| T2                                                                                                                                                                                                | Tumor causing bone erosion or destruction including extension into the hard palate and/or  middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates                     |
| T3                                                                                                                                                                                                | Tumor invades any of the following: bone of the posterior wall of maxillary sinus,  subcutaneous tissues, floor or medial wall of orbit, pterygoid fossa, ethmoid sinuses                                      |
| T4a                                                                                                                                                                                               | Moderately advanced local disease Tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa,  cribriform plate, sphenoid or frontal sinuses                                |
| T4b                                                                                                                                                                                               | Very advanced local disease Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial  nerves other than maxillary division of trigeminal nerve (V2), nasopharynx or clivus |
| Nasal Cavity and Ethmoid Sinus T1 Tumor restricted to any one subsite, with or without bony invasion T2 Tumor invading two subsites in a single region or extending to involve an adjacent region |                                                                                                                                                                                                                |  
59 RTOG 3501 version date: 9/27/16  
| within the nasoethmoidal complex, with or without bony invasion   |                                                                                                              |
|-------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|
| T3                                                                | Tumor extends to invade the medial wall or floor of the orbit, maxillary sinus, palate, or  cribriform plate |  
| Tumor invades any of the following: anterior orbital contents, skin of nose or cheek, minimal  extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than V2, nasopharynx, or clivus  
| PHARYNX Nasopharynx T1   | Tumor confined to the nasopharynx, or tumor extends to oropharynx and/or nasal cavity with  out parapharyngeal extension*                                  |
|--------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| T2                       | Tumor with parapharyngeal extension*                                                                                                                       |
| T3                       | Tumor involves bony structures of skull base and/or paranasal sinuses                                                                                      |
| T4                       | Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, or  with extension to the infratemporal fossa/masticator space |  
*Note: Parapharyngeal extension denotes posterolateral infiltration of tumor.  
| Oropharynx T1   | Tumor 2 cm or less in greatest dimension                                                                                                            |
|-----------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|
| T2              | Tumor more than 2 cm but not more than 4 cm in greatest dimension                                                                                   |
| T3              | Tumor more than 4 cm in greatest dimension or extension to lingual surface of epiglottis                                                            |
| T4a             | Moderately advanced local disease Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or  mandible*                |
| T4b             | Very advanced local disease Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or  encases carotid artery |  
*Note: Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not constitute invasion of larynx.  
| T1   | Tumor limited to one subsite of hypopharynx and/or 2 cm or less in greatest dimension                                                                                                                                                                                                                                           |
|------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| T2   | Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures more  than 2 cm but not more than 4 cm in greatest diameter without fixation of hemilarynx                                                                                                                                                  |
| T3   | Tumor measures more than 4 cm in greatest dimension or with fixation of hemilarynx or  extension to esophagus Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus or central  compartment soft tissue.* Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures |  
*Note: Central compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat.  
| LARYNX Supraglottis T1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Tumor limited to one subsite of supraglottis with normal vocal cord mobility                                                                                                                                                                                           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| T2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region  outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform  sinus) without fixation of the larynx                                       |
| T3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid  area, pre-epiglottic tissues, paraglottic space, and/or inner cortex of thyroid cartilage                                                                           |
| T4a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Moderately advanced local disease Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g.,  trachea, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles,  thyroid, or esophagus)                 |
| T4b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Very advanced local disease Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures                                                                                                                                                |
| Glottis T1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Tumor limited to the vocal cord(s) [may involve anterior or posterior commissure] with normal  mobility                                                                                                                                                                |
| T1a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Tumor limited to one vocal cord                                                                                                                                                                                                                                        |
| T1b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Tumor involves both vocal cords                                                                                                                                                                                                                                        |
| T2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility                                                                                                                                                                              |
| T3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Tumor limited to the larynx with vocal cord fixation, and/or invasion of paraglottic space,  and/or inner cortex of the thyroid cartilage                                                                                                                              |
| T4a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Moderately advanced local disease Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond  the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue,  strap muscles, thyroid, or esophagus) |
| T4b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Very advanced local disease Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.                                                                                                                                               |
| Subglottis T1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Tumor limited to the subglottis                                                                                                                                                                                                                                        |
| T2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Tumor extends to vocal cord(s) with normal or impaired mobility                                                                                                                                                                                                        |
| T3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Tumor limited to larynx with vocal cord fixation                                                                                                                                                                                                                       |
| T4a                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Moderately advanced local disease Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g.,  trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles,  thyroid, or esophagus)                     |
| T4b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Very advanced local disease Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.                                                                                                                                               |
| REGIONAL LYMPH NODES (N) Excluding Nasopharynx NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral node, 3 cm or less in greatest dimension N2 Metastasis in a single ipsilateral node, more than 3 cm, but not more than 6 cm in greatest  dimension, or in multiple ipsilateral lymph nodes, none greater than 6 cm in greatest  dimension, or bilateral or contralateral nodes, none more than 6 cm in greatest dimension N2a Metastasis in a single ipsilateral node more than 3 cm, but not more than 6 cm in greatest  62 RTOG 3501 version date: 9/27/16 |                                                                                                                                                                                                                                                                        |  
| dimension                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                  |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|
| N2b                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Metastasis in multiple ipsilateral nodes, none more than 6 cm in greatest dimension              |
| N2c                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest  dimension |
| N3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Metastases in a lymph node, more than 6 cm in greatest dimension                                 |
| REGIONAL LYMPH NODES (N) Nasopharynx NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Unilateral metastasis in lymph node(s), 3 cm or less in greatest dimension N2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in  greatest dimension, or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest  dimension N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in  greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest  dimension N3 Metastasis in a lymph node, more than 6 cm in greatest dimension   DISTANT METASTASIS (M) |                                                                                                  |  
M0 No distant metastasis M1 Distant metastasis  
| STAGE GROUPING, Excluding Nasopharynx   | STAGE GROUPING Nasopharynx   |           |                              |
|-----------------------------------------|------------------------------|-----------|------------------------------|
| Stage 0                                 | Tis, N0, M0                  | Stage 0   | Tis, N0, M0                  |
| Stage I                                 | T1, N0, M0                   | Stage I   | T1, N0, M0                   |
| Stage II                                | T2, N0, M0                   | Stage II  | T2, N0, M0                   |
| Stage III                               | T3, N0, M0                   | Stage III | T1-T3, N1, M0                |
| T1-3, N1, M0                            | T3, N0, M0                   |           |                              |
| Stage IVA                               | T4a, N0-1, M0                | Stage IVA | T4a, N0-2, M0                |
| Any T, N2, M0                           | T1-3, N2, MO                 |           |                              |
| Stage IVB                               | T4b, Any N, MO               | Stage IVB | Any T, N3, M0 T4b, Any N, M0 |
| Any T, N3, M0                           |                              |           |                              |
| Stage IVC                               | Any T, Any N, M1             | Stage IVC | Any T, Any N, M1             |  
Biospecimen Bank at UCSF Instructions for FFPE Specimen Plug Kit Collection Blood Collection Kit Instructions
appendix iii
shipping instructions

U.S. Postal Service Mailing Address: For Non-urgent FFPE or Non-frozen Specimens Only Biospecimen Bank at UCSF University of California San Francisco Campus Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS): For Frozen or Urgent FFPE samples and Trackable Specimens Biospecimen Bank at UCSF 2340 Sutter Street, Room S341 (Box 1800)
San Francisco, CA 94115 Include all RTOG paperwork in pocket of biohazard bag.  
Check that the Specimen Transmittal Form (STF) has the consent boxes checked off. Check that all samples are labeled with the RTOG study and case number, and include date of collection as well as collection time point (e.g., pretreatment, post-treatment).  
**FFPE Specimens:**
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top of the container. If you can hear the slides shaking it is likely that they will break during shipping.  
o All specimens must be clearly labeled with pathology accession number and block ID. A corresponding H&E stained slide must be submitted with all blocks and unstained slides. Incomplete submissions without H&E slides will be returned to sites to correct before they can be processed.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you shake the container the blocks are not shaking. If you can hear shaking, it is likely that they will break during shipping.  
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address (94115). **Do NOT** ship on Dry Ice.
appendix iii
frozen specimens

o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and clearly identified.  
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7 lbs).  
There should be plenty of dry ice under and above the specimens. If the volume of specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two separate boxes. Any Styrofoam box can be used, as long as it is big enough.  
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and the site will be notified.  
o Send frozen specimens via overnight courier to the address above. Specimens should only be shipped Monday through Wednesday (Monday-Tuesday for Canada) to prevent thawing due to delivery delays.  
Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen at -80 C until ready to ship.  
For Questions regarding collection/shipping please contact the Biospecimen Bank at UCSF by email: RTOG@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-5271.
appendix iv (continued) (8/13/15) ffpe
frozen specimens

This Kit allows sub-sampling of an FFPE block for submission to the Biospecimen Bank at UCSF. The  
  
plug kit contains a shipping tube and a punch tool.  
Step 1 If the block is stored cold, allow it to equilibrate for 30 minutes at room temperature. Place the punch tool on the paraffin block over the selected tumor area. (Ask a pathologist to select area with tumor.) Push the punch into the paraffin block. Twist the punch tool once around to separate the plug from the block. Then pull the punch tool out of the block. The punch should be filled with tissue sample.  
Step 2 Label the punch tool with the proper specimen ID (study number, case number, pathology accession, and block number). DON'T remove specimen from the punch.  
Use a separate punch tool for every specimen. Call or e-mail us if you have any questions or need additional specimen plug kits.  
Step 3 Embed the punches into one block, and cut an H&E from it. For sites unable to embed the punches, once punch tool is labeled, place in shipping tube and mail to address below. Please do not mix specimens in the same tube.  
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID.  
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please send the entire block to the Biospecimen Bank at UCSF, and we will sample a plug from the block and return the remaining block to your facility. Please indicate on the submission form the request to perform the plug procedure and return of the block and provide a return air bill.  
Ship punch block or specimen in punch tool, and all paperwork to the address below. For Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact the Biospecimen Bank at UCSF by e-mail: RTOG@ucsf.edu or call 415-476-7864/Fax 415-476-5271.  
U.S. Postal Service Mailing Address: For Non-urgent, Non-frozen Specimens Only Biospecimen Bank at UCSF University of California San Francisco Campus Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS): For Frozen Specimens or Urgent, Trackable shipments Biospecimen Bank at UCSF
2340 Sutter Street, Room S341 (Box 1800)
San Francisco, CA 94115
appendix iv (continued)
frozen specimens

BLOOD COLLECTION KIT INSTRUCTIONS (8/13/15)
This Kit is for collection, processing, storage, and shipping of plasma or whole blood *(as specified by the* protocol): Kit contents:
Twenty-nine (29) 1 ml cryovials for ALL TIME POINTS Biohazard bags (4) and Absorbent shipping material (4) 1 Styrofoam container (inner) and Cardboard shipping (outer) box UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers Specimen Transmittal (ST) Form and Kit Instructions
appendix iv (continued)
preparation and processing of serum

Label as many 1ml cryovials (5 to 8) as necessary for the plasma collected. Label them with the RTOG study and case number, collection date, time, and time point, and clearly mark cryovials "plasma".  
Process:
1. After collection, into an EDTA blood draw tube (not provided in kit unless requested) invert tube(s)
multiple times to ensure adequate mixing of EDTA.  
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM
for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the ST Form.  
3. If the interval between specimen collection and processing is anticipated to be more than one hour, keep specimen on ice until centrifuging is performed.  
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are necessary for the plasma collected (5 to 8) labeled with RTOG study and case numbers, collection date/time, time point collected and clearly mark specimen as "plasma". Avoid pipetting up the buffy coat layer. If an aliquot has < 0.5 ml in the tube, please note the volume on the vial and also note it on the ST Form.  
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C.  
6. Store frozen plasma until ready to ship on dry ice. 7. See below for storage conditions.  
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the ST Form.
appendix iv (continued) blood collection
(b) whole blood for dna

Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with the RTOG study and case number, collection date/time, and time point, and clearly mark cryovials "blood".  
Process:
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be mixed for 5 minutes on a mixer at room temperature.  
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the blood collected (3 to 5) labeled with RTOG study and case numbers, collection date/time, time point collected and clearly mark specimen as "blood". **If an aliquot has < 1.0 ml in the tube, please note**
the volume on the vial and also note it on the ST Form.  
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius.  
4. Store blood samples frozen until ready to ship on dry ice. 5. See below for storage conditions.
appendix iv (continued) blood collection
please make sure that every

Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen.  
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available, Samples can be stored short term in a -20C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only).  
OR:
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please ship out on Monday-Wednesday only; Canada: Monday-Tuesday only).  
OR:
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; Canada: Monday-Tuesday only).  
Please indicate on Specimen Transmittal Form the storage conditions used and time stored.
appendix iv (continued) blood collection
shipping address

Courier Address (FedEx, UPS): For all Frozen Specimens Biospecimen Bank at UCSF University of California San Francisco 2340 Sutter Street, Room S341 (Box 1800) San Francisco, CA 94115 For questions, call 415-476-7864 or e-mail: RTOG@ucsf.edu
appendix iv (continued) blood collection
shipping/mailing

Ship specimens on Dry Ice overnight Monday-Wednesday **(Monday-Tuesday from Canada)** to prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
Include all RTOG paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box.  
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods together) in absorbent shipping material and place each specimen type in a separate biohazard bag. Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  
Add padding to avoid the dry ice from breaking the tubes.  
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 stickers to outer cardboard box.  
*Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that* there is enough room for plenty of dry ice. *Add padding to avoid the dry ice from breaking the tubes.*
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail RTOG@ucsf.edu or call (415)476-7864.
appendix iv (continued) blood collection
appendix v diarrhea management guidelines

Presented in the sections below are the recommended guidelines for the management of diarrhea in patients receiving lapatinib-based therapy; these guidelines were derived from the recommendations published by the ASCO panel (Benson, 2004).  
Early identification and intervention is critical for the optimal management of diarrhea. A patient's baseline bowel patterns should be established so that changes in patterns can be identified while patient is on treatment.  
It is strongly recommended to give patients receiving lapatinib-based therapy a prescription of loperamide with instructions to start loperamide at the onset of diarrhea as per the recommendations outlined below.
appendix iv (continued) blood collection
patients should be instructed to

An assessment of frequency, consistency and duration as well as knowledge of other symptoms such as fever, cramping, pain, nausea, vomiting, dizziness and thirst should be taken at baseline. Consequently patients at high risk of diarrhea can be identified. Patients should be educated on signs and symptoms of diarrhea with instructions to report any changes in bowel patterns to the physician.  
It is recommended that patients keep a diary and record the number of diarrhea episodes and its characteristics.  
They should also include information on any dietary changes or other observations that may be useful in the evaluation of their diarrhea history. If patients present with diarrhea of any Grade, check they are taking lapatinib correctly, i.e. single daily dose, rather than splitting it through the day. Obtain information on food (solid and liquid) and over the counter (OTC) medication, including herbal supplements, taken during the lapatinib treatment period.
appendix iv (continued) blood collection
definitions

Define diarrhea compared to baseline (Table 1).  
| Table 1                           |                                                                                                                                                                                                |
|-----------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Adverse Event  Grade, CTCAE  v. 4 | Diarrhea                                                                                                                                                                                       |
| 1                                 | Increase of <4 stools/day over baseline; mild increase in ostomy output compared to  baseline                                                                                                  |
| 2                                 | Increase of 4-6 stools/day over baseline; moderate increase in ostomy output  compared to baseline;                                                                                            |
| 3                                 | Increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated;  severe increase in ostomy output compared to baseline; limiting self care activities of  daily living (ADL) |
| 4                                 | Life-threatening consequences; urgent intervention indicated                                                                                                                                   |
| 5                                 | Death                                                                                                                                                                                          |
appendix iv (continued) blood collection
appendix v (continued)

Uncomplicated diarrhea is considered mild-to-moderate and defined as CTCAE v. 4 grade 1 or 2 with no complicating signs or symptoms.  
Complicated diarrhea is severe and defined as any CTCAE v. 4 grade 3 or 4 diarrhea, or grade 1 or 2 with one or more of the following signs or symptoms:
Moderate to severe abdominal cramping Nausea/vomiting ≥Grade2 Decreased performance status Fever Sepsis Neutropenia Frank bleeding (red blood in stool)
Dehydration
appendix iv (continued) blood collection
management guidelines for patients receiving

I. CTCAE Grade 1 NOTE: Patient should be instructed to start supportive care immediately at the first episode of diarrhea (i.e., unformed stool) and call their physician.  
1. Administer loperamide a. Initial dose 4mg followed by 2mg after every unformed stool. Re-evaluate after 24 hours, if:
i. Diarrhea is resolving:
Continue loperamide treatment at 2mg dose after every unformed stool until diarrhea free (i.e., <Grade 1/bowel patterns returned to baseline) for 12 hours.  
If diarrhea recurs, re-initiate loperamide treatment as needed to maintain normal bowel patterns ii. Diarrhea is not resolving:
Administer loperamide at 2mg every 4 hours for the next 24 hour. Re-evaluate after 24 hours. If diarrhea is resolving, administer loperamide at 2mg after every unformed stool until diarrhea free (i.e., <Grade 1/bowel patterns returned to baseline) for 12 hours. If diarrhea is not resolving continue loperamide treatment at 2mg every 4 hours and re-evaluate every 24 hours.  
b. If Grade 1 diarrhea persists for more than 1 week with loperamide treatment, consider treatment with second-line agents (octreotide, budesonide or tincture of opium).  
2. Dietary modifications which are essential in the management of diarrhea include the following recommendations (American Cancer Society; National Cancer Institute): a. Stop all lactose containing products and eat small meals b. Avoid spicy, fried and fatty foods, raw vegetables and other foods high in fiber i. Eat foods low in fiber (i.e., lean meat, rice, skinless chicken or turkey, fish, eggs, canned or cooked skinless fruits, cooked/pureed vegetables)
c. Avoid caffeine and alcohol as they can irritate the bowel and increase motility d. Hydration: Drink 8-10 large glasses of clear liquids a day (e.g., water, electrolyte drink).  
i. Avoid acidic drinks such as tomato juice and fizzy soft drinks e. Supplement diet to include foods rich in potassium (e.g., bananas, potatoes, and apricots) ,
evaluate their impact on diarrhea due to the fiber content (e.g., apricots)  
3. Continue with study treatment (i.e. lapatinib-based treatment)
Continue with supportive care until diarrhea has resolved (diarrhea free for 12 hours/bowel pattern return to baseline). Once diarrhea has resolved, the patient can begin to gradually reintroduce foods from their normal diet.
If diarrhea recurs following stopping of loperamide treatment, resume loperamide treatment at the dose and schedule recommended above and re-introduce diet modifications. Continue with study treatment.  
If grade 1 diarrhea persists for ≥ 2 weeks, refer to the management guidelines for persistent grade 2 diarrhea.
appendix iv (continued) blood collection
ii. ctcae grade 2 note

1. Administer loperamide a. Initial dose 4mg followed by 2mg every 4 hours or after every unformed stool. Re-evaluate after 24 hours. If:
i. Diarrhea is resolving, continue loperamide treatment at 2mg dose after every unformed stool until diarrhea free (i.e., <Grade 1/bowel patterns returned to baseline) for 12 hours If diarrhea recurs, re-initiate loperamide treatment as needed to maintain normal bowel patterns ii. Diarrhea is not resolving, consider loperamide dose of 2mg every 2 hours for 24 hours. If Grade 2 diarrhea persists after total of 48 hours of loperamide treatment, start second-line agents (octreotide, budesonide or tincture of opium).  
Consider performing stool work-up, CBC, electrolytes and other tests as appropriate 2. Dietary modifications which are essential in the management of diarrhea include the following recommendations (American Cancer Society; National Cancer Institute): a. Stop all lactose containing products and eat small meals b. Avoid spicy, fried and fatty foods, bran, raw vegetables and other foods high in fiber i. Eat foods low in fiber (i.e., lean meat, rice, skinless chicken or turkey, fish, eggs, canned or cooked skinless fruits, cooked/pureed vegetables)
c. Avoid caffeine and alcohol as they can irritate the bowel and increase motility d. Hydration: Drink 8-10 large glasses of clear liquids a day (e.g., water, electrolyte drink).  
i. Avoid acidic drinks such as tomato juice and fizzy soft drinks e. Supplement diet to include foods rich in potassium (e.g., bananas, potatoes, and apricots),
evaluate their impact on diarrhea due to the fiber content (e.g., apricots)
3. Continue with study treatment (i.e., lapatinib-based treatment)
Continue with supportive care until diarrhea has resolved (diarrhea free for 12 hours/bowel pattern return to baseline). Once diarrhea has resolved, the patient can begin to gradually reintroduce foods from their normal diet. Refer to Section IV "Recurrent Diarrhea" for study treatment guidelines.
If diarrhea recurs following stopping of loperamide treatment, resume loperamide treatment at the dose and schedule recommended above and re-introduce diet modifications.
appendix iv (continued) blood collection
appendix v (continued)

III. **Persistent (≥ 3days/72 hours) Grade 2 Diarrhea**: hold lapatinib and chemotherapy (if applicable) until diarrhea resolves (<Grade 1/return to baseline bowl pattern). If supportive care measures an 1. If supportive care measures and the interruption of study treatment (i.e., lapatinib and if applicable chemotherapy) are ineffective in treating persistent Grade 1 or Grade 2 diarrhea, perform stool work-up, CBC, electrolytes and other tests as appropriate, consider consulting with a gastrointestinal (GI) specialist. a. After diarrhea resolves (≤Grade 1), resume treatment with lapatinib and chemotherapy (if applicable).  
IV. Recurrent Diarrhea **(more than 1 occurrence of Grade 2 diarrhea):** once the 2nd occurrence of grade 2 diarrhea resolves to ≤ grade 1, consider reducing the dose of lapatinib by 250mg or 1 tablet, unless the lapatinib dose already had been reduced to 750mg. No further dose reduction is recommended for patients taking lapatinib at 750mg.  
1. Consider a dose reduction for chemotherapy (if applicable)
appendix iv (continued) blood collection
b) complicated diarrhea

I. CTCAE, v 4 grade 3 or Grade 1 or 2 with complicating features (severe cramping, severe nausea/vomiting, decreased performance status, fever, sepsis, Grade 3 or 4 neutropenia, frank bleeding, dehydration)
1. Patient **must** call physician immediately for any complicated severe diarrhea event 2. If loperamide has not been initiated, initiate loperamide immediately: Initial dose 4mg followed by 2mg every 2 hours or after every unformed stool 3. Refer to the dietary modification recommendations for Grade 1 and Grade 2 uncomplicated diarrhea 4. For dehydration use intravenous fluids as appropriate, if patient presents with severe dehydration administer octreotide 5. Perform stool work-up, CBC, electrolytes and other tests as appropriate 6. Administer antibiotics as needed (example fluoroquinolones), especially if diarrhea is persistent beyond 24 hours or there is fever or Grade 3-4 neutropenia 7. Hold lapatinib and chemotherapy (if applicable) until symptoms resolve to ≤Grade 1 and reintroduce lapatinib at a reduced dose (unless dose had been reduced to 750mg, contact medical monitor for further guidance) a. Consider a dose reduction for chemotherapy (if applicable)
8. Supportive care and other interventions should be continued until diarrhea free (i.e., <Grade 1/bowel patterns returned to baseline) for 24 hours 9. Intervention may require hospitalization for patients most at risk for life threatening complications
appendix iv (continued) blood collection
ii. ctcae v. 4 grade

1. Patient must call physician immediately for any Grade 4 diarrhea event 2. Discontinue treatment with lapatinib, hold chemotherapy (if applicable)
3. If loperamide has not been initiated, initiate loperamide immediately: Initial dose 4mg followed by 2mg every 2 hours or after every unformed stool 4. For dehydration use intravenous fluids as appropriate, if patient presents with severe dehydration administer octreotide 5. Perform stool work-up, CBC, electrolyte and other tests as appropriate 6. Recommend consulting with GI specialist 7. Administer antibiotics as needed (example fluoroquinolones), especially if diarrhea is persistent beyond 24 hours or there is fever or Grade 3/4 neutropenia 8. Supportive care and other intervention should be continued until diarrhea free (i.e., <Grade 1/bowel patterns returned to baseline) for 24 hours 9. Intervention may require hospitalization for patients most at risk for life threatening complications Refer to and follow the recommended supportive care guidelines in the previous sections and as depicted in Figure 1 (see next page).
appendix iv (continued) blood collection
appendix vi (2/2/16) prohibited medications

Lapatinib is a substrate for CYP3A4. Inducers and inhibitors of CYP3A4 may alter the metabolism of lapatinib.  
The following list of CYP3A4 inducers and inhibitors are prohibited from screening through discontinuation from study.  
| Drug Class                                   | Specific Agents                                                                                                                                                                                                            | Wash-out1                       |             |
|----------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|-------------|
| CYP3A4 Inducers rifamycin antibiotics        | rifampicin, rifabutin, rifapentine                                                                                                                                                                                         |                                 |             |
| anticonvulsants                              | phenytoin, carbamezepine, barbiturates (e.g.,  phenobarbital)                                                                                                                                                              |                                 |             |
| antiretrovirals                              | efavirenz, nevirapine, tipranivir, etravirine cortisone (>50 mg), hydrocortisone (>40 mg),  prednisone or prednisolone (>10 mg),  methylprednisolone or triamcinolone (>8 mg),  betamethasone or dexamethasone (>1.5  mg)2 | 2 weeks                         |             |
| glucocortical steroids (oral only) Note: Steroids are  required as an anti-emetic  for cisplatin. The shortterm administration of  steroids for this indication  poses minimal risk related  to CYP3A4. other                                              | St. John's Wort, modafinil                                                                                                                                                                                                 |                                 |             |
| CYP3A4 Inhibitors antibiotics                | clarithromycin, erythromycin, troleandomycin,  flucloxacillin                                                                                                                                                              |                                 |             |
| antifungals                                  | itraconazole,                                                                                                                                                                                                              | ketoconazole,                   | fluconazole |
| (>150 mg daily), voriconazole                |                                                                                                                                                                                                                            |                                 |             |
| antiretrovirals                              | delaviridine, nelfinavir, amprenavir, ritonavir,                                                                                                                                                                           | 1 week                          |             |
| indinavir, saquinavir, lopinavir, atazanavir |                                                                                                                                                                                                                            |                                 |             |
| calcium channel blockers                     | verapamil, diltiazem                                                                                                                                                                                                       |                                 |             |
| antidepressants                              | nefazodone, fluvoxamine                                                                                                                                                                                                    |                                 |             |
| gastrointestinal agents3                     | cimetidine                                                                                                                                                                                                                 |                                 |             |
| fruit juices                                 | grapefruit, star fruit, and papaw                                                                                                                                                                                          |                                 |             |
| other                                        | amiodarone                                                                                                                                                                                                                 | 6 months                        |             |
| Miscellaneous antacids                       | Mylanta, Maalox, Tums, Rennies                                                                                                                                                                                             | 1 hour before and  after dosing |             |
| herbal supplements4                          | ginkgo biloba, kava, grape seed, valerian,                                                                                                                                                                                 | 2 weeks                         |             |
| ginseng, echinacea, evening primrose oil     |                                                                                                                                                                                                                            |                                 |             |  
1. Time period between last dose of listed drug and first dose of lapatinib, required to avoid drug-drug interaction potential for toxicity (inhibitors) or loss of efficacy (inducers) that could make the patient unevaluable. Clinically appropriate substitution of drugs not on the list is recommended.  
2. A standard 3-5 day course of dexamethasone at a dose following the institutions standard of care for the prevention and/or treatment of platinum-induced nausea and vomiting is allowed. Glucocortical steroid oral dose equivalents (in parentheses) to dexamethasone 1.5 mg (or less) given daily are allowed. Intravenous dosing should be considered if clinically appropriate.  
3. Emetogenic chemotherapy may require 3-4 daily doses of aprepitant. CYP3A4 inhibition by oral (not IV) aprepitant may require a concurrent dose reduction of 1-2 lapatinib tablets.  
4. This list is not all-inclusive; therefore, for herbal supplements not listed, please contact a Novartis Medical Monitor or Clinical Scientist.  
NOTE: If future changes are made to the list of prohibited medications, formal documentation will be created and stored with the study file. Any changes will be communicated to the investigative sites in the form of a letter.
appendix vii management of dental
appendix vi (2/2/16) prohibited medications

Dental Care for Irradiated Patients Goals for a dental care program include: 1. To reduce incidence of bone necrosis.  
2. To reduce incidence of irradiation caries. 3. To allow proper fitting of dentures following treatment. Pre-irradiation Care and Procedures The patients may be grouped into four groups in accordance with the problems they present prior to irradiation.  
Group 1 Includes edentulous patients. They may require surgical removal of any symptomatic cysts, infected retained root tips, or alveolar hyperplasia. These patients require hygiene instruction and precautionary instruction about trauma with premature use of a prosthesis.
appendix vii management of dental
group 2

Includes those with poor dental hygiene, including those patients whose teeth are beyond repair by ordinary dental procedure, those with generalized oral sepsis, those with generalized periodontal disease, and those with chronic periapical abscesses or granulomas.  
Procedures performed on this group include removal of all remaining teeth prior to irradiation with primary closure and surgical preparation of the alveolar ridges to laterally support a prosthesis. There should be antibiotic coverage during the healing stage and adequate time prior to the start of radiation therapy. These patients need complete hygiene instruction and precautionary instruction about premature use of a prosthesis.
appendix vii management of dental
group 3

Includes those in whom dental condition is fair, including those patients whose teeth are restored, ordinary dental procedures, periodontal pockets are less than 3 mm deep, carious lesions are not in proximity to the pulp, and no more than 20 restorable carious lesions are present. X-ray examinations show at least 1/2 of the bone still present around root surfaces. These patients require removal of any teeth that are non-salvageable in accordance with the above and restorations of the remaining teeth as required. The patients are instructed for dental prophylaxis and the patients utilize custom-made fluoride carriers.
appendix vii management of dental
group 4

Includes those in whom dental hygiene is good. This includes patients who do not have severe malocclusion in whom few carious lesions are present. Carious lesions are not in close proximity to the pulp and are correctable by conventional methods. These patients require periodontal evaluation and dental prophylaxis training, restorations as needed, no extractions prior to radiation therapy, and fitting for custom carriers.
appendix vii management of dental
extraction of teeth

If extraction of teeth is necessary prior to radiation therapy, the bone must be contoured so that closure at the extraction site is possible. All loose spicules and sharp projections must be removed. The approximation of the gingival tissue must be such that the closure is neither too loose nor too tight. At least 10 days are required for adequate healing prior to initiation of therapy.  
Causative Factors The major causative factors appear to be the reduction of the amount of saliva and secondarily, reduced pH in the mouth. This occurs following high dose radiation to the major salivary glands using parallel opposed fields. The decay process usually occurs in the first year following radiation therapy. It tends to occur more quickly in teeth which have a large amount of root cementum exposed to those teeth with large amounts of plaque formation present. Doses of radiation in excess of 20 Gy to salivary tissue place the teeth at risk.
appendix vii management of dental
appendix vii (continued)

Preventive Program The rationale behind the use of fluoride treatments is to make the tooth surfaces less susceptible to the decay process. This is accomplished by a combination of increasing fluoride concentration on the tooth surface and by the effect of fluoride on the plaque and flora that are present in the oral cavity. Adequate results are obtained by:
1) cleansing the teeth thoroughly, followed by a good home care dental prophylaxis program, 2) construction of fluoride carriers, custom-made mouth guards, which provide local application of fluoride solution to the gingiva and tooth surfaces. Fluoride carriers are made individually with the use of casts. Material used for making a mouth guard is "Sta-Guard" plastic used in conjunction with vacutrole unit produced by Jelrus Technical Products, Corp., both of which are available through local dental supply. This material is molded to the cast impression and allowed to harden. A fluoride solution prepared at the M.D. Anderson Hospital is now available from the Emerson Laboratories, Inc., Dallas, Texas 75221. It has been used to coat the plastic carrier for use in the mouth. The patients are instructed to cleanse their teeth prior to placement of the carrier. It is then worn in place for 5 minutes each day. The patients are instructed to rinse their mouths thoroughly following the use of the carrier. This will be continued for an indefinite period of time. Close follow-up is necessary.
appendix vii management of dental
results

In the 5-1/2 year program at the M.D. Anderson Hospital beginning in 1966, a study of 304 patients shows that the incidence of necrosis of the jaw was reduced to approximately 21% compared to 37% prior to initiation of the study. Groups 3 and 4 patients randomized with and without fluoride treatment showed reduction in radiation carries from 67% to 34% among Group 3 patients, and from 65% to 22% among Group 4 patients.
appendix vii management of dental
failure to control decay

Management of failure to control radiation decay includes silver fillings with continued use of fluoride treatments.  
If the decay process is sufficiently advanced that a filling will no longer stay in place, these teeth are merely smoothed so that there will be no sharp, irritating edges. The mere existence of such a decayed tooth is not necessarily reason for extraction, for it must be remembered that extraction could lead to complications such as bone necrosis.  
Pulp exposure resulting from the decay process can usually be handled by use of antibiotics and/or root-canal therapy. Hypersensitivity of Teeth Occasionally, a patient will exhibit extreme sensitivity of the teeth secondary to diminished amounts of saliva. This has been shown to be reduced in incidence with the fluoride treatments. Should this problem become manifest, increasing the fluoride treatment to 10 to 15 minutes 3 times a day is recommended. Infections Infections occurring in patients under or after radiation therapy are best managed conservatively with good oral hygiene, irrigation and flushing procedures, and systemic antibiotics.
appendix vii management of dental
bone necrosis

The patients receiving radiation therapy to a high dose to the head and neck region have increased susceptibility to bone necrosis for several reasons including: impairment of normal metabolism, increased susceptibility to infection and severely limited repair process. Bone necrosis occurs most often after dental or oral surgery in patients who have been previously radiated. Conservative management should be tried first, though in more aggressive lesions a more radical approach may ultimately be necessary.