radiation therapy oncology group rtog
7.1.4 comprehensive adverse events and

The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. *Frequency is provided based on 2571 patients.* Below is the CAEPR for Sorafenib
(BAY 43-9006; Nexavar).  
NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| Version 2.10, June 24, 20201                                                |                                     |                                                                            |
|-----------------------------------------------------------------------------|-------------------------------------|----------------------------------------------------------------------------|
| Adverse Events with Possible                                                |                                     |                                                                            |
| Relationship to Sorafenib (BAY 43-9006; Nexavar) (CTCAE 5.0 Term) [n= 2571] | Specific Protocol                   |                                                                            |
| Exceptions to Expedited  Reporting (SPEER)                                  |                                     |                                                                            |
| Likely (>20%)                                                               | Less Likely (<=20%)                 | Rare but Serious (<3%)                                                     |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                                 | Anemia (Gr 3)                       |                                                                            |
| CARDIAC DISORDERS                                                           | Chest pain - cardiac                | Heart failure Left ventricular systolic  dysfunction Myocardial infarction |
| GASTROINTESTINAL DISORDERS Abdominal pain                                   | Abdominal pain (Gr 3)               |                                                                            |
| Ascites Constipation                                                        | Constipation (Gr 2)                 |                                                                            |
| Diarrhea                                                                    | Diarrhea (Gr 3)                     |                                                                            |
| Gastrointestinal hemorrhage2                                                | Gastrointestinal hemorrhage2 (Gr 3) |                                                                            |
| Gastrointestinal perforation3                                               |                                     |                                                                            |  
| Adverse Events with Possible                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                     |                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|------------------------|
| Relationship to Sorafenib (BAY 43-9006; Nexavar) (CTCAE 5.0 Term) [n= 2571]                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Specific Protocol   |                        |
| Exceptions to Expedited  Reporting (SPEER)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                     |                        |
| Likely (>20%)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Less Likely (<=20%) | Rare but Serious (<3%) |
| Mucositis oral                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                     |                        |
| Nausea                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Nausea (Gr 3)       |                        |
| Vomiting                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Vomiting (Gr 3)     |                        |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema limbs Fatigue                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Fatigue (Gr 3)      |                        |
| Fever                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Fever (Gr 2)        |                        |
| HEPATOBILIARY DISORDERS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Hepatic failure     |                        |
| IMMUNE SYSTEM DISORDERS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Anaphylaxis         |                        |
| INFECTIONS AND INFESTATIONS Infection4 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Injury, poisoning and  procedural complications -  Other, specify (wound healing  complication) INVESTIGATIONS Activated partial thromboplastin  Activated partial thromboplastin  time prolonged time prolonged (Gr 2) Alanine aminotransferase  Alanine aminotransferase  increased increased (Gr 3) Alkaline phosphatase increased Alkaline phosphatase increased  (Gr 3) Aspartate aminotransferase  Aspartate aminotransferase  increased increased (Gr 3) Blood bilirubin increased Blood bilirubin increased (Gr 3) Creatinine increased Creatinine increased (Gr 3) Electrocardiogram QT  corrected interval prolonged GGT increased INR increased INR increased (Gr 3) Investigations - Other  (Bicarbonate-serum low) Lipase increased Lipase increased (Gr 3) Lymphocyte count decreased Lymphocyte count decreased  (Gr 3) Neutrophil count decreased Neutrophil count decreased (Gr  4) Platelet count decreased Platelet count decreased (Gr 4) Serum amylase increased Serum amylase increased (Gr 3) Thyroid stimulating hormone  increased Weight loss Weight loss (Gr 2) White blood cell decreased White blood cell decreased (Gr  4) METABOLISM AND NUTRITION DISORDERS Anorexia Anorexia (Gr 3) |                     |                        |  
| Adverse Events with Possible                                                                                                                             |                                     |                        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|------------------------|
| Relationship to Sorafenib (BAY 43-9006; Nexavar) (CTCAE 5.0 Term) [n= 2571]                                                                              | Specific Protocol                   |                        |
| Exceptions to Expedited  Reporting (SPEER)                                                                                                               |                                     |                        |
| Likely (>20%)                                                                                                                                            | Less Likely (<=20%)                 | Rare but Serious (<3%) |
| Hypercalcemia                                                                                                                                            |                                     |                        |
| Hyperglycemia                                                                                                                                            | Hyperglycemia (Gr 3)                |                        |
| Hyperkalemia                                                                                                                                             | Hyperkalemia (Gr 3)                 |                        |
| Hypernatremia                                                                                                                                            |                                     |                        |
| Hypoalbuminemia                                                                                                                                          | Hypoalbuminemia (Gr 3)              |                        |
| Hypocalcemia                                                                                                                                             | Hypocalcemia (Gr 3)                 |                        |
| Hypoglycemia                                                                                                                                             | Hypoglycemia (Gr 2)                 |                        |
| Hypokalemia                                                                                                                                              | Hypokalemia (Gr 3)                  |                        |
| Hyponatremia                                                                                                                                             | Hyponatremia (Gr 3)                 |                        |
| Hypophosphatemia                                                                                                                                         | Hypophosphatemia (Gr 3)             |                        |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia                                                                                               | Arthralgia (Gr 3)                   |                        |
| Back pain                                                                                                                                                | Back pain (Gr 3)                    |                        |
| Bone pain Muscle cramp Myalgia Pain in extremity                                                                                                         | Pain in extremity (Gr 3)            |                        |
| NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND  POLYPS) Treatment related secondary  malignancy NERVOUS SYSTEM DISORDERS Dizziness Headache | Headache (Gr 3)                     |                        |
| Intracranial hemorrhage Reversible posterior  leukoencephalopathy  syndrome                                                                              |                                     |                        |
| PSYCHIATRIC DISORDERS                                                                                                                                    | Insomnia                            |                        |
| RENAL AND URINARY DISORDERS Acute kidney injury RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough                                                    | Cough (Gr 2)                        |                        |
| Dyspnea                                                                                                                                                  | Dyspnea (Gr 3)                      |                        |
| Respiratory hemorrhage5 Voice alteration                                                                                                                 |                                     |                        |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia                                                                                                          | Alopecia (Gr 2)                     |                        |
| Dry skin                                                                                                                                                 | Dry skin (Gr 2)                     |                        |
| Erythema multiforme                                                                                                                                      |                                     |                        |
| Palmar-plantar                                                                                                                                           | Palmar-plantar                      |                        |
| erythrodysesthesia syndrome                                                                                                                              | erythrodysesthesia syndrome  (Gr 3) |                        |
| Pruritus                                                                                                                                                 | Pruritus (Gr 3)                     |                        |
| Rash maculo-papular                                                                                                                                      | Rash maculo-papular (Gr 3)          |                        |
| Stevens-Johnson syndrome Toxic epidermal necrolysis                                                                                                      |                                     |                        |  
Adverse Events with Possible  
  
Specific Protocol  
  
  
  
  
Exceptions to Expedited Reporting (SPEER)  
| [n= 2571]            | Reporting (SPEER)   |                        |
|----------------------|---------------------|------------------------|
| Likely (>20%)        | Less Likely (<=20%) | Rare but Serious (<3%) |
| Hypertension         | Hypertension (Gr 3) |                        |
| Thromboembolic event |                     |                        |  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Gastrointestinal hemorrhage may include Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL
DISORDERS SOC.  
3Gastrointestinal perforation may include Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC.  
4Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 5Respiratory hemorrhage may include bronchopulmonary hemorrhage, epistaxis, laryngeal hemorrhage, mediastinal hemorrhage, pharyngeal hemorrhage, and pleural hemorrhage under the RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC.  
6Febrile neutropenia is seen mostly in combination with other agents.  
Adverse events reported on sorafenib (BAY 43-9006; Nexavar) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that sorafenib (BAY 439006, Nexavar) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other
(Thrombotic microangiopathy (e.g., TTP or HUS)); Febrile neutropenia6 CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Palpitations; Pericardial effusion; Pericarditis; Right ventricular dysfunction; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia; Ventricular arrhythmia; Ventricular tachycardia EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus ENDOCRINE DISORDERS - Adrenal insufficiency; Hyperthyroidism; Hypothyroidism EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other
(color vision deficits); Eye disorders - Other (light to dark adaptation); Eye disorders - Other (retinal vein occlusion, bilat); Eye disorders - Other (retinal hemorrhage); Eye disorders - Other (visual field distortion); Flashing lights; Keratitis; Photophobia; Retinal detachment GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fistula; Anal mucositis; Anal pain; Anal ulcer; Cheilitis; Colitis; Colonic obstruction; Colonic ulcer; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophageal pain; Esophagitis; Flatulence; Gastric ulcer; Gastritis; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other (small bowel NOS fistula); Gastrointestinal fistula; Hemorrhoids; Ileal fistula; Ileus; Oral pain; Pancreatitis; Proctitis; Rectal fistula; Rectal mucositis; Rectal obstruction; Rectal pain; Small intestinal obstruction; Stomach pain; Visceral arterial ischemia GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Facial pain; Flu like symptoms; Localized edema; Multi-organ failure; Non-cardiac chest pain; Pain HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic hemorrhage; Hepatobiliary disorders - Other
(biliary obstruction secondary to multiple biliary stones)
IMMUNE SYSTEM DISORDERS - Allergic reaction; Cytokine release syndrome; Immune system disorders - Other (systemic inflammatory response syndrome)
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Fall; Fracture; Hip fracture; Vascular access complication; Wound dehiscence INVESTIGATIONS - CPK increased; Cardiac troponin I increased; Cardiac troponin T increased; Cholesterol high; Ejection fraction decreased; Fibrinogen decreased; Investigations - Other (blood urea nitrogen high)
METABOLISM AND NUTRITION DISORDERS - Acidosis; Alkalosis; Dehydration; Hypermagnesemia; Hypertriglyceridemia; Hyperuricemia; Hypomagnesemia; Tumor lysis syndrome MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; Generalized muscle weakness; Joint range of motion decreased; Muscle weakness lower limb; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other (cramping); Myositis; Neck pain NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia secondary to oncology chemotherapy; Myelodysplastic syndrome; Tumor hemorrhage; Tumor pain NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of consciousness; Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Hydrocephalus; Ischemia cerebrovascular; Lethargy; Leukoencephalopathy; Memory impairment; Muscle weakness left-sided; Muscle weakness right-sided; Neuralgia; Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Stroke; Syncope; Tremor; Vasovagal reaction PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Libido decreased; Personality change; Psychosis RENAL AND URINARY DISORDERS - Chronic kidney disease; Hematuria; Nephrotic syndrome; Proteinuria; Renal and urinary disorders - Other (focal segmental glomerulosclerosis); Renal and urinary disorders - Other (right ureter rupture); Renal calculi; Renal hemorrhage; Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urine discoloration REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Gynecomastia; Hematosalpinx; Menorrhagia; Ovarian hemorrhage; Prostatic hemorrhage; Spermatic cord hemorrhage; Testicular hemorrhage; Uterine hemorrhage; Vaginal fistula; Vaginal hemorrhage RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; Allergic rhinitis; Bronchospasm; Hiccups; Hoarseness; Hypoxia; Laryngeal mucositis; Pharyngeal mucositis; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary edema; Pulmonary fibrosis; Respiratory, thoracic and mediastinal disorders - Other (nasal septal perforation);
Tracheal mucositis SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythroderma; Hyperhidrosis; Nail loss; Pain of skin; Purpura; Rash acneiform; Scalp pain; Skin and subcutaneous tissue disorders - Other (non-life threatening squamous cell carcinoma of skin: keratocanthomas type); Skin hyperpigmentation; Skin hypopigmentation; Skin ulceration; Urticaria VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypotension; Phlebitis; Vascular disorders
- Other (ruptured aortic aneurysm); Vasculitis Note: Sorafenib (BAY 43-9006; Nexavar) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
Chronic concomitant administration of rifampin with a single dose of sorafenib resulted in a 24% decrease in the combined AUC of sorafenib and its active primary metabolite when rifampin was co-administered with sorafenib. The clinical significance of this overall decrease in drug exposure is unknown. Other inducers of CYP3A4 activity (eg, hypericum perforatum [also known as St. John's wort], phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase the metabolism of sorafenib and decrease **its exposure.**
- *CYP2C9 Substrates* The possible effect of sorafenib on warfarin, a CYP2C9 substrate, was assessed in sorafenib-treated patients compared to placebo-treated patients. The concomitant treatment with sorafenib and warfarin did not result in changes in mean PT-INR compared to placebo. However, patients taking warfarin should have their INR checked regularly (see Product Monograph: WARNINGS AND PRECAUTIONS
and PART II: DETAILED PHARMACOLOGY).  
- *CYP Isoform-selective Substrates* Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are substrates of cytochromes CYP3A4, CYP2D6 and CYP2C19, respectively, following 4 weeks of sorafenib administration did not alter the exposure of these agents. This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes. Therefore, clinical pharmacokinetic interactions of sorafenib with substrates of these enzymes are unlikely.  
- *UGT1A9 Inhibitors* An in vitro study has revealed a number of drugs affected UGT1A9-mediated sorafenib glucuronidation with an IC50 value below 100 μM. They were atorvastatin (IC50 = 67 μM), ketoconazole (87 μM), mefenamic acid (28 μM), erlotinib (69 μM), and niflumic acid (1.2 μM). T
he clinical relevance of these drug interactions has not been tested.  
- *Combination with Other Antineoplastic Agents* Sorafenib is approved only as monotherapy in the treatment of RCC and HCC (see Product Monograph: INDICATIONS AND CLINICAL USE). In clinical studies, sorafenib has been administered together with a variety of other antineoplastic agents at their commonly-used dosing regimens, including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway, there was a 67-120% increase in the AUC of SN-38 and a 26-42% increase in the AUC of irinotecan. The clinical significance of these findings is unknown (see Product Monograph: WARNINGS AND PRECAUTIONS). A clinical study has revealed that administration of sorafenib with a 3-day break in dosing around administration of docetaxel resulted in a 36-80% increase in docetaxel AUC and a 16-32% increase in docetaxel Cmax (see Product Monograph: WARNINGS AND PRECAUTIONS).  
7.1.6 Storage Store at controlled room temperature (15ºC - 25ºC). Storage conditions should not exceed 25ºC. Stability The stability profile of the solid drug is excellent. In solid form, sorafenib is stable at room temperature for up to 24 months, and it is insensitive to light. The expiration date should be readily available on the label of commercially supplied sorafenib.  
7.2 Dose Modifications (27Oct2017)
NOTE: The dose modifications are recommended modifications. The final dosing should be based on the investigator's discretion taking into account the patient's entire clinical picture. The goal is that the patient will stay on the drug for as long as possible (even if reduced dose) if there is clinical benefit, no progression and the patient is tolerating sorafenib.  
Protocol treatment may be dose modified based on criteria outlined in the dose modification table
(Section 7.2.3). For both arms, after each cycle (28 days), assessment for toxicity will be made. The sorafenib will be continued at the present dose (or escalated to full dose during cycle \#2 or subsequent cycles for arm 2) if there is no dose limiting toxicity requiring dose reduction as per Section 7.2.3, the Child score is Child Pugh ≤7 and the treating physician recommends continuation. If the Child Pugh score is B7, and the patient is otherwise suitable for sorafenib, sorafenib should be delivered at half dose. If at subsequent evaluations demonstrate recovery to CP <= 6 and no other competing toxicity then Sorafenib can be re-escalated to full dose. For both arms, it is not the intention to take patients off sorafenib early for minor changes in liver function.  
7.2.1 Once reduced for toxicity, Sorafenib may or may not be re-escalated per the investigator's discretion. If dose reductions beyond dose level -2 are required or drug is held for more than 3 weeks, all protocol therapy will be discontinued. If more than one of these apply, use the most stringent (i.e., the greatest dose reduction).  
7.2.2 Dose Reduction Table  
| Dose level 0 (starting dose, 800 mg po)   | 2 x 200 mg po every 12 hours   |
|-------------------------------------------|--------------------------------|
| Dose level -1 (400 mg po)                 | 1 x 200 mg po every 12 hours   |
| Dose level -2 (200 mg po)                 | 1 x 200 mg po daily            |  
7.2.3 Dose Modification Table NOTE: The dose modifications are recommended as minimum required modifications. The final dosing should be based on the investigator's discretion taking into account the patient's entire clinical picture. The goal is that the patient will stay on the drug for as long as possible (even if reduced dose) if there is clinical benefit, no progression and the patient is tolerating sorafenib.  
| TOXICITY                                         | MODIFICATION                                                                                                                                                                                                           |
|--------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Hematologic Toxicities                           |                                                                                                                                                                                                                        |
| grade 1 or 2                                     | Continue sorafenib                                                                                                                                                                                                     |
| grade 3                                          | Continue sorafenib at one reduced dose level                                                                                                                                                                           |
| grade 4 or neutropenic fever                     | Interrupt sorafenib until ≤ grade 2, then continue  at one reduced dose level                                                                                                                                          |
| Gastrointestinal Toxicities                      |                                                                                                                                                                                                                        |
| grade 1 or 2                                     | Continue sorafenib                                                                                                                                                                                                     |
| grade ≥ 3 diarrhea                               | Interrupt sorafenib until improves to ≤ grade 2,  then resume sorafenib at one reduced dose level                                                                                                                      |
| grade ≥ 3 nausea or vomiting despite antiemetics | Interrupt sorafenib until improves to ≤ grade 2,  then resume sorafenib at one reduced dose level                                                                                                                      |
| Hepatic Dysfunction                              |                                                                                                                                                                                                                        |
| bilirubin 1.3-3.0                                | Continue sorafenib                                                                                                                                                                                                     |
| bilirubin > 3.0                                  | Discontinue sorafenib                                                                                                                                                                                                  |
| Child-Pugh score > 7                             | Interrupt sorafenib until improved to Child-Pugh  score 7 or less. Sorafenib is to be re-started at  half dose, if Child-Pugh score is B7, and it can be  re-escalated to full dose if Child-Pugh score  returns to A. |  
| Skin Toxicity: Rash (Maculo-Papular) or                           |                                                                                                             |
|-------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------|
| Hand-Foot Skin Reaction (HFSR; Palmar-Plantar Erythrodysesthesia) |                                                                                                             |
| grade 1                                                           | Continue sorafenib                                                                                          |
| grade 2, 1st appearance                                           | Interrupt sorafenib until improves to ≤ grade 1,  then resume sorafenib at the previous dose level          |
| grade 2, 2nd or 3rd appearance                                    | Interrupt sorafenib until improves to ≤ grade 1,  then resume sorafenib at one reduced dose level           |
| grade 2, 4th appearance                                           | Discontinue sorafenib therapy                                                                               |
| grade 3, 1st or 2nd appearance                                    | Interrupt sorafenib until toxicity improves to  ≤ grade 1, then resume sorafenib at one reduced  dose level |
| grade 3, 3rd appearance                                           | Discontinue sorafenib therapy                                                                               |  
Following a full cycle (one month) of redu**ced dose sorafenib with no rash or HFSR of ≥ grade 1** severity, the dose of sorafenib may be re-escalated to the previous dose level. (Note: Re-escalation is allowed only in the case of skin toxicity.)  
| Hypertension                                |                                                                                                                   |
|---------------------------------------------|-------------------------------------------------------------------------------------------------------------------|
| hypertension controlled with medication (to | Continue sorafenib                                                                                                |
| <140/90) hypertension >140/90 and ≤160/100  | Continue sorafenib Consider adding or adjusting anti-hypertensive  medications                                    |
| persistent (>160/100) or symptomatic        | Interrupt sorafenib                                                                                               |
| hypertension                                | Resume when blood pressure improves to  <160/100 If sorafenib is interrupted for ≥3 weeks,  discontinue sorafenib |
| grade 4                                     | Discontinue sorafenib therapy                                                                                     |
| Other non-Hematologic Toxicities            |                                                                                                                   |
| grade 1, 2                                  | Continue sorafenib                                                                                                |
| grade 3                                     | Interrupt sorafenib until toxicity resolves to ≤ grade  1, then reduce by one dose level                          |
| grade 4                                     | Discontinue sorafenib therapy                                                                                     |  
7.2.4 Toxicity Management Management of Skin Toxicity: At first occurrence of HFSR, independent of grade, supportive measures such as topical emollients, low potency steroids, or urea-containing cream should be administered.  
7.3 Modality Review (8/26/14)
The Medical Oncology Co-Chairs, Andrew Zhu, MD and/or Jennifer Knox, MD, will perform a Systemic Therapy Assurance Review of patients who receive protocol-specified systemic therapy in this trial. The goal of the review is to evaluate protocol compliance. The review process is contingent on timely submission of systemic therapy treatment data as specified in Section 12.1.  
The scoring mechanism is: **Per Protocol/Acceptable Variation, Not Per Protocol, and Not** Evaluable. A report is sent to each institution once per year to notify the institution about compliance for each case reviewed in that year. This Systemic Therapy Assurance Review will be performed on an ongoing basis (for example, the first review after NRG Oncology receives complete data for 20 cases and the next review after NRG Oncology receives complete data for 20 more cases). The final cases will be reviewed within 3 months after this study has reached the target accrual or as soon as NRG Oncology receives complete data for all cases, whichever occurs first.  
7.4 Adverse Events **(13-MAY-2019)**
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for all AE reporting, CTEP-AERS, and case report forms. CTCAE version 5.0 will be utilized for CTEP-AERS reporting beginning April 1, 2018; all study case report forms will continue to use CTCAE version 4.0. All appropriate treatment areas should have access to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from the CTEP web site (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)
7.4.1 Adverse Events (AEs)
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6).  
7.4.2 Serious Adverse Events (SAEs) - Serious adverse events (SAEs) that meet expedited reporting criteria defined in the table in section 7.5 will be reported via CTEP-AERS. SAEs that require 24 hour CTEP-AERS notification are defined in the expedited reporting table in section 7.5. **Contact**
the CTEP-AERS **Help Desk if assistance is required.**  
Definition of an SAE: Any adverse experience occurring during any part of protocol treatment and 30 days after that results in any of the following outcomes:
Death; A life-threatening adverse drug experience; Inpatient hospitalization or prolongation of existing hospitalization; A persistent or significant disability/incapacity; A congenital anomaly/birth defect; Important medical events that may not result in death, be life threatening, or require hospitalization may be considered an SAE, when, based upon medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in the definition.
Due to risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy of a study participant must be reported via CTEP-AERS in anexpedited manner.
radiation therapy oncology group rtog
7.4.3 acute myeloid leukemia (aml)

AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS system within 30 days of AML/MDS diagnosis. Secondary Malignancy A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
- Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])
- Myelodysplastic syndrome (MDS) - Treatment-related secondary malignancy
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol. Second Malignancy A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via CDUS unless otherwise specified.  
7.5 CTEP-AERS **Expedited Reporting Requirements** (27Oct2017)
All serious adverse events that meet expedited reporting criteria defined in the reporting table below will be reported via CTEP-AERS, the Adverse Event Expedited Reporting System, accessed via the CTEP web site, https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG Oncology requirements for expedited adverse event reporting.  
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only pathway.  
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to the NRG Oncology Operations Office at 215-574-3191, for instances when Internet fails. Once internet connectivity is restored, an AE report submitted by phone must be entered electronically into CTEP-AERS.  
- CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification is electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS
24-hour notification must be followed by a CTEP-AERS 5 Calendar Day Report. Serious adverse events that require 24 hour CTEP-AERS notification are defined in the expedited reporting table below.  
- Supporting source documentation is requested by NRG as needed to complete adverse event review. Supporting source documentation should include the protocol number, patient ID number, and CTEP-AERS ticket number on each page. Contact NRG Oncology at 1-215574-3191 for details to submit source documentation.  
- A serious adverse event that meets expedited reporting criteria outlined in the following table but is assessed by the CTEP-AERS System as "expedited reporting NOT required" must still be reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the "NOT Required" assessment; the CTEP-AERS System allows submission of all reports regardless of the results of the assessment.  
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the table below. **Important:** All AEs reported via CTEP-AERS also must be reported on the AE
section of the appropriate case report form (see Section 12.1). Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur within 30 Days of the Last Administration of the Commercially Available Agent 1, 2
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fda reporting requirements for serious

NOTE: Investigators **MUST** immediately report to the sponsor (NCI) **ANY** Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 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 to the NCI via CTEPAERS within the timeframes detailed in the table below.  
| Hospitalization               | Grade 1          | Timeframes       | Grade 3 Timeframes   | Grade 4 & 5   |
|-------------------------------|------------------|------------------|----------------------|---------------|
| Grade 2                       |                  |                  |                      |               |
| Timeframes                    | Timeframes       |                  |                      |               |
| Resulting in  Hospitalization | 10 Calendar Days |                  |                      |               |
| ≥ 24 hrs                      | 24-Hour 5        |                  |                      |               |
| Not resulting in              | Calendar Days    |                  |                      |               |
| Hospitalization               | Not required     | 10 Calendar Days |                      |               |
| ≥ 24 hrs                      |                  |                  |                      |               |  
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR
Expedited AE reporting timelines are defined as:
o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24hour report.  
o "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE.  
1Serious adverse events that occur more than 30 days after the last administration of commercially available agent 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 2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above applies after this reporting period.  
Effective Date: May 5, 2011
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9.2 non-permitted supportive therapy (27oct2017)

9.2.1 Anticoagulants are not recommended to be used to treat HCC related vascular thrombosis. They may be used for bland thrombosis or pulmonary emboli.
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10.0 tissue/specimen submission (27oct2017) patients

the study, such as tissue/specimen submission or quality of life assessment. 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. **Note:** Sites are not permitted to delete the tissue/specimen component from the protocol or from the sample consent.  
10.1 **Tissue/Specimen Submission**
The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved through careful block storage and processing. NRG Oncology encourages participants in protocol studies to consent to the banking of their tissue. NRG Oncology Biospecimen Bank 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. In this study, tissue will be submitted to the NRG Oncology Biospecimen Bank for the purpose of tissue banking and translational research (recommended).  
10.2 Specimen Collection for Tissue Banking and **Translational Research** (27Oct2017)
For patients who have consented to participate in the tissue/blood component of the study. The following must be provided in order for the case to be evaluable for the Biospecimen Bank - San Francisco.  
10.2.1 One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic slide (block); it does not have to be the diagnostic slide itself).  
10.2.2 A corresponding paraffin-embedded tissue block of the tumor (preferred, the block must match the H&E being submitted) or 10 unstained slides (5 micron cut onto positive charged slides) of tumor tissue. Block or slides must be clearly labeled with the pathology identification number and block number that corresponds to the Pathology Report.
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9.0 other therapy 9.1 permitted

9.1.1 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.  
9.1.2 Antiemetics (e.g. dopamine (D2) receptor antagonist or 5HT3 antagonists) should be considered to be used prior to each fraction of SBRT to prevent nausea if the stomach is anticipated to receive any radiation. They may also be used for symptomatic nausea or vomiting.  
9.1.3 Antidiarrheals may be used to treat therapy induced diarrhea. 9.1.4 H2 blockers or proton pump inhibitors are strongly recommended if 20 Gy or more is delivered to the luminal gastrointestinal tract or at the treating physicians discretion. They should start before completion of SBRT and continue for at least 6 months.  
9.1.5 Analgesics may be used to treat tumor or therapy induced pain. NSAIDS are recommended to be avoided to reduce luminal GI irritation.  
9.1.6 In the occurrence of liver toxicity (including classic RILD, non-classic RILD or any CTCAE 4.0 grade 4 toxicity or any sorafenib associated liver toxicity, occurring in the absence of HCC progression within 12 weeks of completion of radiation therapy), best supportive care and possible diuretics are recommended. Steroids may be used, and a referral to a hepatologist is recommended.  
9.1.7 Topical creams, emollients, balms, low potency steroids or urea containing creams are recommended for discomfort due to hand foot syndrome.  
9.1.8 Anti-hypertensives should be used for sorafenib-induced increase in blood pressure. Calcium channel blockers are recommended.  
- 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.  
10.2.3 A Pathology Report documenting that the submitted block or slides contains tumor. The report must include the NRG Oncology 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.  
10.2.4 A Specimen Transmittal (ST) Form clearly stating that tissue is being submitted for the NRG
Oncology Biospecimen Bank - San Francisco; if for translational research, this should be stated on the form. The form must include the NRG Oncology protocol number and patient's case number.
For specimen collection: See Appendix IX for the specimen collection kits and instructions. The following materials must be provided to the NRG Oncology Biospecimen Bank - San Francisco:
An ST documenting the date of collection of the biospecimen; the NRG Oncology protocol number, the patient's case number, time point of study, and method of storage, for example, stored at -80° C, must be included.  
10.2.5 Storage Conditions Store frozen specimens at -80° C (-70°C to -90°C) until ready to ship. If a -80°C Freezer is not available:
- Samples can be stored short term in a -20° C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only; Canada: MondayTuesday).  
OR:
- Samples can be stored in plenty of dry ice for up to one week, replenishing daily
(ship out Monday-Wednesday only; Canada: Monday-Tuesday).  
OR:
- Samples can be stored in liquid nitrogen vapor phase (ship out MondayWednesday only; Canada: Monday-Tuesday).  
Please indicate on the ST Form the storage conditions used and time stored.  
10.2.6 Specimen Collection Summary  
| Specimens for Tissue Banking/Translational Research                                            |                           |                                                                                                                                         |                                                                                      |
|------------------------------------------------------------------------------------------------|---------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|
| Specimens taken from                                                                           | Collected when:           | Submitted as:                                                                                                                           | Shipped:                                                                             |
| patient:                                                                                       |                           |                                                                                                                                         |                                                                                      |
| Representative H&E  stained slides of the  primary tumor                                       | Pre-treatment             | H&E stained slide                                                                                                                       | Slide shipped ambient to NRGBB-SF                                                    |
| A paraffin-embedded  tissue block of the  primary tumor taken  before initiation of  treatment | Pre-treatment             | Paraffin-embedded  tissue block. If a block  is not available then 10 unstained slides  (5 micron cut onto  positively charged  slides) | Block or slides shipped  ambient                                                     |
| SERUM: 5-10 mL of  whole blood in 1 red-top  tube and centrifuge                               | Pre-treatment  (baseline) | Frozen serum  samples containing a  minimum of 0.5 mL  per aliquot in 1 mL  cryovials (five)                                            | Serum sent frozen on  dry ice via overnight  carrier to NRGBB-SF in  batch shipments |
| 1 and 3 months from  study entry                                                               |                           |                                                                                                                                         |                                                                                      |
| PLASMA: 5-10 mL of                                                                             | Pre-treatment             | Frozen plasma                                                                                                                           | Plasma sent frozen on                                                                |  
| anticoagulated whole  blood in EDTA tube #1  (purple/ lavender top)  and centrifuge                            | (baseline)                                                                                                                                                                | samples containing a  minimum of 0.5 mL  per aliquot in 1 mL  cryovials (five)       | dry ice via overnight  carrier to NRGBB-SF in  batch shipments                              |
|----------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|
| 1 and 3 months from  study entry  At the time of  progression and/or  grade 4 liver toxicity  (within 4 weeks) |                                                                                                                                                                           |                                                                                      |                                                                                             |
| Whole blood for DNA: 5- 10 mL of anticoagulated  whole blood in EDTA  tube #2 (purple/lavender  top) and mix   | Pre-treatment Note: If site missed this  collection time point  they may collect whole  blood for DNA at a later  time point instead but  must note this on the  ST Form. | Frozen whole blood  samples containing 1-2 mL per aliquot in  2 mL cryovials (three) | Whole blood sent  frozen on dry ice via  overnight carrier to  NRGBB-SF in batch  shipments |  
10.2.7 Submit materials for Tissue Banking and Translational Research as follows:
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u. s. postal service mailing

Courier Address (FedEx, UPS, etc.): For Frozen Specimens NRG Oncology **Biospecimen Bank**
University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA **94115**  
Questions: 415-476-7864/FAX 415-476-5271; NRGBB@ucsf.edu  
10.3 Confidentiality/Storage **(13-MAY-2019)**
10.3.1 Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient's case number only. The NRG Oncology Biospecimen Bank 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.  
10.3.2 Specimens for tissue banking will be stored for an indefinite period of time. 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.
11.0 **PATIENT ASSESSMENTS**
Patients must be offered the opportunity to participate in the correlative components of the study, such as quality of life (QOL) assessment. If the patient consents to participate in the QOL component of the study, sites are required to administer the baseline QOL and functional assessments prior to the start of protocol treatment.  
11.1 **Study Parameters**
See Appendix I. Timing of all follow-up imaging and other assessments is from registration for both arms of the study.  
11.2 Evaluation During Treatment 11.2.1 Once PD has occurred, patients need to follow the study on-treatment calendar. Documentation of all subsequent therapies should occur. The follow-up schedule post-treatment is outlined in Appendix I.  
11.3 **Measurement of Response (**25-MAR-2020) 11.3.1 **See Appendix I** (Study Parameter Table). Note, response in the irradiated volume is challenging to assess before 3 months post radiation therapy due to radiation change in the surrounding liver. Even at 3 months, changes in the surrounding liver around the HCC may represent radiation treatment change, rather than tumor progression. Thus, review of images by experienced radiologists is required, as is importance of relaying radiation information to the radiologists, to avoid inaccurate labeling of progression when liver changes are due to radiation effect on the liver. It is strongly recommended to use the same method of assessment (i.e. comparable scanners and imaging techniques) from one scan to the subsequent scans. For example, multi-phasic CT scans should be used with the same slice thickness for each follow-up scan. It would not be appropriate to compare a pre-treatment non-contrast liver MRI on a 0.5T scanner with 0.5 cm slice thickness to a post-treatment gadolinium enhanced MRI on a 3T scanner with 0.2 cm slice thickness (nor vice versa). If a patient develops a contraindication to CT IV contrast, then contrast MR may be used to follow the patient. If a patient develops a contraindication to MR IV contrast, then non-contrast MR and/or US is recommended for follow-up. Imaging details are outlined in Appendix V.  
11.3.2 Response will be evaluated in this study using the international criteria proposed in the Reviewed Response Evaluation Criteria in Solid Tumors (RECIST) Guideline version 1.1 (Eur J Cancer:
2009: 45:228-247). Response will be assessed locally, with no planned central review. Overall response will be measured (based on assessment of target lesions), as well as irradiated lesion response (defined as response of the target measurable disease included in the radiation volume). Response measurements, including response assessment of tumor thrombosis as per Section 11.3.3, will take place every 3 months, according to the schedule in Appendix I.  
Measurable disease is defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded), e.g. liver lesions ≥ 10mm by CT scan with slice thickness no greater than 5 mm, nodes ≥ 15mm in short axis by CT. All tumor measurements should be recorded in millimeters.  
Non-measurable disease is defined as all other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or pathologic lymph node ≥ 10mm and ≤ 15 mm) and any vascular thrombosis. Other non-measureable disease includes ascites, pleural effusions.  
- *Response criteria: Evaluation of target lesions* Target lesions: All measureable lesions up to a maximum of two lesions per organ and five lesions in total, representative of all involved organs. Target lesions should be selected on the basis of their size (longest diameters) and their suitability for accurate repeated measurements. Vascular thrombi will not be included as target lesions. Target irradiated lesions (for SBRT arm only): All measureable lesions up to a maximum of two lesions in the liver, within the irradiated volume. Target lesions should be selected on the basis of their size (longest diameters) and their suitability for accurate repeated measurements. The sum of longest diameters (in any dimension) of target lesions will be used to characterize the objective tumor response. Vascular thrombi will not be included as target irradiated lesion, unless vascular HCC is the only HCC present, in which case it can be used as the target lesion. Response for vascular thrombi will follow Section 11.3.3. Complete response (CR): Disappearance of all measurable target lesions. Any pathological nodes (whether target or non-target) must have reduction in short axis to < 10mm.  
Partial response (PR): At least 30% decrease in the sum of the longest diameters of the target lesions, taking as reference the baseline sum diameters.  
Progressive disease (PD): At least 20% increase in sum of the longest diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
The appearance of one or more new lesions is also considered progression. Unequivocal, unambiguous progression of non-measurable disease is included as PD. For vascular thrombosis (consistent with Section 11.3.3), this is defined as:
a) Unequivocal, unambiguous new enhancing tumor thrombosis or b) Unequivocal, unambiguous increase in the volume of enhancing portion of thrombosis Stable disease (SD): No change or small changes that do not meet the above criteria for PR or PD, taking as reference the smallest sum diameters while on study.  
11.3.3 Vascular Thrombosis Response There are no validated guidelines to monitor and report vascular thrombosis response.  
Consistent with RECIST1.1, thrombosis will be considered non-measurable disease. Response of vascular thrombosis will be recorded as a secondary endpoint in this study, using the following guidelines:
CR thrombosis: Complete resolution of thrombosis, with recanalization of vessel.  
PR thrombosis: any of a) Partial recanalization of thrombosis (if prior complete blockage)
b) Unequivocal reduction in the maximal girth of thrombosis c) Unequivocal reduction in the volume, or elimination, of arterial enhancing portion of thrombosis PD thrombosis: any unequivocal, unambiguous, a) New enhancing tumor thrombosis b) Increase in the volume of enhancing portion of thrombosis Note that for "unequivocal progression" of thrombosis (non-measurable disease), the increase in overall tumor burden (enhancing thrombosis) must be comparable to the increase required for RECIST1.1 definition of PD of measurable disease (e.g. at least 73% increase in volume, which is similar to 20% increase in diameter, and at least a 5 mm absolute increase).  
SD thrombosis: any of a) No change or small changes that do not meet the above criteria for PR or PD,
taking as reference the smallest sum diameters while on study.  
b) Increase in the volume of non-enhancing thrombosis c) New bland non-enhancing thrombosis
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11.4 criteria for discontinuation of

11.4.1 Protocol treatment may be discontinued for any of the following reasons:
- Progression of disease, as defined in Section 11.3. Note that there are no accepted guidelines for assessing progression or response of vascular HCC to therapy. Thus, discontinuation of protocol treatment should only occur in reaction to changes in vascular thrombosis response if the progression is unequivocal and of substantial magnitude (estimated > 73% increase in volume of enhancing vascular HCC and > 5 mm absolute increase) and the investigator believes discontinuation is in the patient's best interest. If there is any doubt about the
'unequivocal' nature of the vascular progression, patients should remain on therapy.  
- Unacceptable adverse event(s), as defined in Section 6.0 and/or 7.0 and/or 13.5.4 - Withdrawal of informed consent (subject's decision to withdraw for any reason)
- Pregnancy - Delay in protocol treatment > 3 weeks, as specified in Section 7.0.  
Reasons for discontinuation from protocol treatment should be documented in the patient's medical record and case report Form (CRF).  
11.4.2 If protocol treatment is discontinued, follow up and data collection will continue as specified in the protocol.  
11.4.3 Any salvage treatment will be recorded. If radiation therapy is offered for salvage post sorafenib in patients not randomized to SBRT, total dose, dose per fraction and overall time should be recorded and reported on the Salvage RT form. In this situation, radiation therapy is only recommended if the patient meets eligibility criteria similar to baseline eligibility of this study.
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11.5 health related quality of

FACT-Hep version 4 is a 45-item self-report instrument designed to measure health-related quality of life (HRQL) in patients with hepatobiliary cancers. The FACT-Hep consists of the 27item FACT-General (FACT-G), which assesses generic QOL concerns, and the newly validated 18-item Hepatobiliary Subscale (HS), which assesses disease-specific issues. Patients are asked to score each item for the past week on a 4-point likert scale (from 0 "not at all" and 4 "very much"). The total FACT-Hep score is the sum of the four sub-scale scores and ranges from 0 to 108; it takes less than 15 minutes to complete and is translated in 45 languages. The FACT-Hep is validated and presents good internal consistency, test–retest reliability, and convergent and discriminate validity in patients with hepatobiliary cancer and HCC Heffernan 2002, Steel 2006, Wang 2007, Steel 2004). 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. Note: The FACT-Hep has been validly translated into many languages and will be available in languages beyond English on the RTOG 1112 page of the CTSU website. Patients eligible for QOL analyses need to provide informed consent, and translated FACT-Hep QOL questionnaires must be available in their primary language.  
FACT-Hep QOL will be administered at baseline, 3 months, 6 months and 12 months post initiation of protocol therapy. Patients will be included in the QOL analyses only if they have provided both baseline and at least 1 subsequent measurement.  
11.5.2 EuroQol (EQ-5D)
The EuroQol (EQ-5D) is a 2-part questionnaire measuring a patient's utility or preference of their health state for the calculation of quality-adjusted survival that takes the patient approximately 5 minutes to complete (Schultz 2002). The first part consists of 5 items covering 5 dimensions, including: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension can be graded on 3 levels including: 1-no problem, 2-moderate problems, and 3extreme problems. There are 243 potential health states. The second part is a visual analogue scale (VAS) valuing current health state, measured on a 20 cm, 10 point-interval scale. Either the index score or the VAS score can be used in the quality-adjusted survival analysis (Wu 2002). The benefit of measuring quality-adjusted survival is that it can be compared to the outcomes of other interventions across disease sites and can be used by health policy makers to rank interventions.  
The EQ-5D will be administered at baseline, 3 months, 6 months and 12 months post initiation of protocol therapy. Patients will be included in the quality-adjusted survival analyses only if they have provided both baseline and at least 1 subsequent measurement.  
11.5.3 Quality-Adjusted Survival The EQ-5D will be used to assess quality-adjusted survival. Quality-adjusted survival is the weighted sum of different time in different health states added up to a total quality-adjusted survival time [U=sum of quality (qi) of health states K times the duration (si) spent in each health state] (Glasziou 1990).
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12.0 data collection 12.1 data

The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered queries and form delinquencies, monitor data quality and timeliness, generate reports, and review metrics. The DQP is located on the CTSU members' website under Data Management. The Rave Home section displays a table providing summary counts of Total Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP
Reports modules are available to access details and reports of unanswered queries, delinquent forms, forms with current status and timeliness reports. Review the DQP
modules on a regular basis to manage specified queries and delinquent forms. The DQP is accessible by site staff that are rostered to a site and have access to the CTSU website. Staff that have Rave study access can access the Rave study data using a direct link on the DQP.
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12.2 data submission / data

Medidata Rave is a clinical data management system being used for data collection for this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role assignments.  
Requirements to access Rave via iMedidata:
- A valid CTEP-IAM account; and
- Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements:
- Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus
(AP) registration type;
- Rave Investigator role must be registered as a Non-Physician Investigator (NPIVR) or Investigator (IVR); and
- Rave Read Only role must have at a minimum an Associates (A) registration type.  
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and documentation required. Upon initial site registration approval for the study in Regulatory Support System (RSS), all persons with Rave roles assigned on the appropriate roster will be sent a study invitation email from iMedidata. To accept the invitation, site staff must either click on the link in the email or log in to iMedidata via the CTSU members' website under *Data Management > Rave Home* and click to *accept* the invitation in the *Tasks* pane located in the upper right corner of the iMedidata screen. Site staff will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (eLearnings)
and can be accessed by clicking on the eLearning link in the *Tasks* pane located in the upper right corner of the iMedidata screen. If an eLearning is required for a study and has not yet been taken, the link to the eLearning will appear under the study name in the *Studies* pane located in the center of the iMedidata screen; once the successful completion of the eLearning has been recorded, access to the study in Rave will be granted, and a *Rave EDC* link will replace the eLearning link under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website in the Rave section under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU
members' website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or e-mail at ctsucontact@westat.com.
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12.2.1 summary of data submission

Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during the trial using Medidata Rave®. Additionally, certain adverse events must be reported in an expedited manner for more timely monitoring of patient safety and care. See Section 7 for information about expedited and routine reporting.  
| Folder                                                                             | Form/Item                                          |                                                 |
|------------------------------------------------------------------------------------|----------------------------------------------------|-------------------------------------------------|
| Registration via the OPEN System                                                   | -                                                  | Subject Enrollment Form                         |
| Enrollment When pushed into RAVE there will  be 5 forms representing  registration | -                                                  | Demography Form                                 |
| -                                                                                  | Step Information Form                              |                                                 |
| -                                                                                  | Treatment Assignment Form                          |                                                 |
| -                                                                                  | Eligibility Checklist Form                         |                                                 |
| Baseline folder                                                                    | -                                                  | Patient History Form (formerly known as the A5) |
| -                                                                                  | Work Up                                            |                                                 |
| -                                                                                  | Other Conditions                                   |                                                 |
| -                                                                                  | Lab Results                                        |                                                 |
| -                                                                                  | Pathology Report (Upload of report is required)    |                                                 |
| -                                                                                  | EQ-5D and FACT-HEP if consented for QOL            |                                                 |
| -                                                                                  | Digital Data (RT Plan)(Arm 2)                      |                                                 |
| -                                                                                  | Pretreatment Scan (Arm 1)                          |                                                 |
| -                                                                                  | Sorafenib Details (if received prior Sorafenib)    |                                                 |
| Month 1 Visit-Arm 1                                                                | -                                                  | Lab Results                                     |
| -                                                                                  | Protocol Specific Adverse Events                   |                                                 |
| -                                                                                  | Other Adverse Events  Sorafenib                    |                                                 |
| Month 1 Visit-Arm 2                                                                | -                                                  | Protocol Specific Adverse Events                |
| -                                                                                  | Other Adverse Events                               |                                                 |
| -                                                                                  | Lab Results                                        |                                                 |
| -                                                                                  | RT Administration Form                             |                                                 |
| -                                                                                  | RT Treatment if was RT administered="yes"          |                                                 |
| -                                                                                  | Protocol Specific RT if was RT  administered="yes" |                                                 |
| Month 2 Visit                                                                      | -                                                  | Lab Results                                     |
| -                                                                                  | Protocol Specific Adverse Events                   |                                                 |
| -                                                                                  | Other Adverse Events Sorafenib                     |                                                 |
| Month 3 and 6 month visit                                                          | -                                                  | Lab Results Sorafenib                           |
| -                                                                                  | Patient Contact                                    |                                                 |  
| -                                    | Followup-if Patient able to be Contacted ="yes"                                                                         |             |
|--------------------------------------|-------------------------------------------------------------------------------------------------------------------------|-------------|
| -                                    | Primary Cause of Death Form - if Patient's Vital  Status = "dead"                                                       |             |
| -                                    | Disease Assessment Form - if Documented  clinical assessment = "yes"                                                    |             |
| -                                    | New Primary Cancer Form - if New Primary  Cancer ="yes"                                                                 |             |
| -                                    | Non-protocol Treatment Form - if patient started  on non-protocol cancer therapy ="yes"                                 |             |
| -                                    | Adverse Event Form/ Protocol Specific Adverse  Events/Other Adverse Events - if new or  continuing adverse events="yes" |             |
| -                                    | Salvage RT-if salvage RT="yes"                                                                                          |             |
| -                                    | EQ-5D/FACT-HEP- if consented to QOL                                                                                     |             |
| Month 4 visit and monthly as long as | -                                                                                                                       | Lab Results |
| Sorafenib is being administered      | -                                                                                                                       | Other Labs  |
| -                                    | Protocol Specific Adverse Events                                                                                        |             |
| -                                    | Other Adverse Events Sorafenib                                                                                          |             |
| Month 9 visit                        | -                                                                                                                       | Lab Results |
| -                                    | Protocol Specific Adverse Events                                                                                        |             |
| -                                    | Other Adverse Events                                                                                                    |             |
| -                                    | Followup Form-if Patient able to be Contacted  ="yes"                                                                   |             |
| -                                    | Primary Cause of Death Form - if Patient's Vital  Status = "dead"                                                       |             |
| -                                    | Disease Assessment Form - if Documented  clinical assessment = "yes"                                                    |             |
| -                                    | New Primary Cancer Form - if New Primary  Cancer ="yes"                                                                 |             |
| -                                    | Non-protocol Treatment Form - if patient started  on non-protocol cancer therapy ="yes"                                 |             |
| -                                    | Protocol Specific Adverse Events                                                                                        |             |
| -                                    | Other Adverse Event- if new or continuing  adverse events="yes"                                                         |             |
| -                                    | Salvage RT-if salvage RT="yes"                                                                                          |             |
| Month 12 visit                       | -                                                                                                                       | Lab Results |
| -                                    | Protocol Specific Adverse Events                                                                                        |             |
| -                                    | Other Adverse Events                                                                                                    |             |
| -                                    | Followup Form-if Patient able to be Contacted  ="yes"                                                                   |             |
| -                                    | Primary Cause of Death Form - if Patient's Vital  Status = "dead"                                                       |             |
| -                                    | Disease Assessment Form - if Documented  clinical assessment = "yes"                                                    |             |
| -                                    | New Primary Cancer Form - if New Primary  Cancer ="yes"                                                                 |             |
| -                                    | Non-protocol Treatment Form - if patient started  on non-protocol cancer therapy ="yes"                                 |             |
| -                                    | Adverse Event Form- if new or continuing  adverse events="yes"                                                          |             |
| -                                    | Salvage RT-if salvage RT=yes                                                                                            |             |
| -                                    | EQ-5D/FACT-HEP- if consented to QOL                                                                                     |             |
| Month 15 and q 3 months              | -                                                                                                                       | Lab Results |  
- *Protocol Specific Adverse Events*  
  
- *Other Adverse Events*
- *Followup Form*-if Patient able to be Contacted
="yes"
- *Primary Cause of Death Form* - if Patient's Vital Status = "dead"
- *Disease Assessment Form* **– if Documented**
clinical assessment = "yes"
- *New Primary Cancer Form* - if New Primary Cancer ="yes"
- *Non-protocol Treatment* Form - if patient started on non-protocol cancer therapy ="yes"
- *Adverse Event Form*- if new or continuing adverse events="yes"
- Salvage RT-if salvage RT="yes"  
| Item                                                                                                                                                                                                                                                         | Due                                                                                                                                                         |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|----|
| Preliminary Dosimetry Information  Digital Data Submission –Treatment Plan, including multiphasic CT and /or MRI                                                                                                                                             | Within 1                                                                                                                                                    |    |
| submitted to TRIAD exported from treatment planning machine by Physicist                                                                                                                                                                                     | week of                                                                                                                                                     |    |
| Digital data submission includes the following:                                                                                                                                                                                                              | start of                                                                                                                                                    |    |
| -                                                                                                                                                                                                                                                            | CT data, critical normal structures, all GTV, CTV, and PTV contours                                                                                         | RT |
| -                                                                                                                                                                                                                                                            | Digital beam geometry for initial and boost beam sets                                                                                                       |    |
| -                                                                                                                                                                                                                                                            | Doses for initial sets of concurrently treated beams                                                                                                        |    |
| -                                                                                                                                                                                                                                                            | Digital DVH data for all required critical normal structures, GTV, CTV, and  PTVs for total dose plan                                                       |    |
| -                                                                                                                                                                                                                                                            | All required structures MUST be labeled per the table in Section 6.5.                                                                                       |    |
| -                                                                                                                                                                                                                                                            | The "RTOG 1112 Datasheet" is available in the Forms section of the RTOG1112 page of the CTSU website. Submit via TRIAD with the digital  data listed above. |    |
| Upon submission of the digital data via TRIAD, complete an online digital  data transmission form located in the Forms section on the web site at  http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1112 Final Dosimetry Information | Within 1                                                                                                                                                    |    |
| Radiotherapy Form                                                                                                                                                                                                                                            | week of                                                                                                                                                     |    |  
12.3 Summary of Dosimetry Digital Data Submission (Submit to TRIAD; see Section 5.5 **for**  
account access and installation instructions) (13-MAY-2019)  
Pre Randomization Scan (All Patients)  
Item Due Preliminary Dosimetry Information (DD)  
Digital Data Submission - Diagnostic or planning CT or MRI obtained within  
28 days prior to registration, include the following  
Within 1 week  
of  
randomization for Arm 1 patients only and arm 2  
patients who  
do not end up having radiation therapy  
| Preliminary Dosimetry Information (DD) Digital Data Submission - Diagnostic or planning CT or MRI obtained within  28 days prior to registration, include the following - Contours of liver and GTV - Volume (cc) of liver minus GTV (>700 cc non-tumor liver  recommended) - Calculation of GTV/(liver including GTV) (80% recommended)   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Daily Treatment Record                                                                                                                           | RT end   |
|--------------------------------------------------------------------------------------------------------------------------------------------------|----------|
| NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM IMAGES AND IGRT DATA WILL BE KEPT BY THE INSTITUTION AND ONLY  SUBMITTED IF REQUESTED. |          |  
NOTE: Copies of simulation and IGRT imaging and the complete RT daily treatment record for the previous original EBRT will be kept by the institution and only submitted if specifically requested.  
13.0 STATISTICAL CONSIDERATIONS 13.1 **Endpoints**
13.1.1 Primary Endpoint Overall survival (failure is death due to *any cause)*
13.1.2 Secondary Endpoints
- Time to progression (failure is defined per Section 11.3)
- Progression free survival (failure is progression or death due to any cause)
- Toxicity: using Common Toxicity Criteria (CTCAE) version 4.0.  
- Vascular thrombosis response - Health Related Quality of Life [measured by the Functional Assessment of Cancer Therapy–Hepatobiliary (FACT-Hep)]
- Quality adjusted survival
13.2 Stratification (8/26/14)
Patients will be stratified before randomization with respect to Vascular involvement (IVC/main portal vein/right or left main branch portal vein vs. other vascular involvement vs. none), Hepatitis
(B or B and C vs. C vs. other), Site (North American vs. non-North American), and HCC volume/liver volume (<10% vs. 10-40 vs. >40%). The treatment allocation scheme described by Zelen (1974) will be used because it balances patient factors other than institution.
radiation therapy oncology group rtog
13.3 sample size and power

13.3.1 The sample size calculations are based on the primary hypothesis that SBRT followed by sorafenib will increase overall survival as compared to sorafenib alone for patients with hepatocellular carcinoma. It is projected that 75% of the accrual will come from North American sites and 25% of the accrual will come from non-North American sites. It is expected that approximately two-thirds of accrual will be patients with vascular thrombosis while one-third will be patients without vascular thrombosis.  
The sorafenib alone control arm median overall survival time (MST) is estimated to be 10.5 months, based on the SHARP sorafenib arm MST of 10.7 months (Llovet 2008) and a recent study of 1073 HCC patients randomized to sorafenib versus sunitinib; the median overall survival time (MST) of the patients in the sorafenib arm was 10.0 months (versus 8.1 in the sunitinib arm)
[Cheng 2011]. Approximately 75% of these patients were Asian-Pacific, demonstrating that outcomes in Asia have improved since the original Asian-Pacific sorafenib randomized trial
(where MST was 6.5 months for sorafenib alone [Cheng 2009]).  
The RT sorafenib combination arm MST is hypothesized to be 14.5 months, based on the Toronto RT alone MST of 17.0 months (Bujold 2012) in 102 patients with advanced HCC treated with RT alone on study, as well as a retrospective study of RT and sunitinib from Taiwan with a MST of 16 months (Chi 2010). Other reports of RT alone for HCC patients with portal vein thrombosis demonstrate a range of MSTs from 10 to 15 months, in the absence of sorafenib.  
The required sample size for the primary endpoint of OS is based on the following conditions:
- OS times are exponentially distributed with (at least approximately) constant hazards in both treatment arms
- The control arm will have a median OS of 10.5 months (monthly hazard of 0.066) - The experimental arm will have a median OS of 14.5 months (monthly hazard of 0.0478)
- Hazard ratio (experimental/control) = 0.72
- One-sided test at α = 0.05
- Statistical power of 80% - 7 years of accrual (post ramp-up) with 1 year of follow-up
- Three interim significance tests and a final test are planned using the HaybittlePeto (Lan 1983; O'Brien 1979) rule for efficacy and a more aggressive futility rule suggested by Weiand et al (1994).  
A total of 264 evaluable patients, using the group sequential design method (Pocock 1977) with 3 interim analyses, will provide the 238 OS events required to determine if the addition of SBRT to sorafenib alone improves overall survival from 10.5 to 14.5 months (HR=0.72). Given the conditions above, and adjusting for ineligible/lost patients or patients that cannot meet the RT
planning requirements, a total sample size of 292 **patients** will be required to be accrued uniformly over 7 years, post ramp-up period, with an additional 1 year of follow-up.  
13.3.2 Patient Accrual Patient accrual is projected to be 3 cases per month, with a ramp-up period in the first 6 months with no projected accrual. Following this ramp-up period, accrual will be completed in 7 years. Projected accrual was based on a survey submitted in June 2011 by the RTOG to all full RTOG
members, the members of the RTOG GI Steering Committee and interested Asian centers. In brief, there were 43 respondents, including the 2 Asian centers. Twenty-eight centers planned to definitely open the study; 22 of these centers are already credentialed for RTOG lung or liver SBRT studies (excluding the 2 Asian centers). An additional 13 centers were considering opening the study (all of these centers were credentialed for RTOG lung or liver SBRT studies).  
Based on the 22 credentialed RTOG non-Asian centers, 12 patients per month were estimated to be accrued to this study. Including the Asian centers, 17 patients per month were estimated to participate. Accounting for some overestimation and lower than expected accrual in prior HCC studies, the actual expected accrual is 3 patients per month.  
If the total accrual during months 13 through 18 of the study is ≥ 50% of the targeted accrual (18 or more cases), then the accrual will have met the NCI-CTEP Ph III accrual guidelines and will continue. If the total accrual during months 13 through 18 of the study is ≤ 20% of the targeted accrual (≤ 7 cases in total), then the protocol will be discontinued per NCI-CTEP accrual guidelines for phase III studies. If the total accrual during months 13 through 18 is between 21%
and 49% (8 to 17 cases), then the protocol will continue to accrue subjects and will be evaluated again at the end of month 24. If the accrual during months 22 through 24 is at least 50% of the targeted accrual (≥ 9 cases in total), the NCI-CTEP accrual guidelines for phase III studies will have been met and the study will continue accrual; otherwise, the study will be discontinued.
radiation therapy oncology group rtog
13.4 power information for health

The Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) will be used to measure HRQOL. Protocol-eligible patients will be included in the QOL analysis only if they have provided baseline and at least one subsequent measurement. The FACT-Hep will be collected on all cases participating in this portion of the trial and will be collected at 4 time points: baseline, 3 months, 6 months, and 12 months post initiation of protocol therapy.  
13.4.1 The primary HRQOL endpoint will be to determine whether patients treated with SBRT and sorafenib have an improved FACT-Hep score from baseline to 6 months, as measured by the proportion of patients on each treatment arm with improvement, defined as an increase in the FACT-Hep score of at least 5 points (minimally important difference), as compared to patients receiving sorafenib alone. The power calculations shown below cover a number of possible proportions for improvement over the control arm. The power calculations are all based on a 1sided, α=0.05, chi-squared test and the listed patient participation rate (PPR) of the 320 evaluable patients required for the overall study.
radiation therapy oncology group rtog
power calculations for fact-hep score

Power  
(64% PPR  
n/arm=85)  
0.10 0.25 91 87 83 0.10 0.30 98 97 95 0.20 0.35 81 76 71 0.20 0.40 95 93 89 0.30 0.45 75 70 65 0.30 0.50 92 89 85 0.40 0.55 73 68 62 0.40 0.60 91 88 84 0.50 0.65 73 67 63 0.50 0.70 92 89 85  
*If the participation rate is higher, there will be more power to detect the hypothesized differences; if the participation rate is lower, there will be less power.  
| Power               |       |       |    |    |
|---------------------|-------|-------|----|----|
| (64% PPR  n/arm=85) |       |       |    |    |
| 0.10                | 0.25  | 91    | 87 | 83 |
| 0.10                | 0.30  | 98    | 97 | 95 |
| 0.20                | 0.35  | 81    | 76 | 71 |
| 0.20                | 0.40  | 95    | 93 | 89 |
| 0.30                | 0.45  | 75    | 70 | 65 |
| 0.30                | 0.50  | 92    | 89 | 85 |
| 0.40                | 0.55  | 73    | 68 | 62 |
| 0.40                | 0.60  | 91    | 88 | 84 |
| 0.50                | 0.65  | 73    | 67 | 63 |
| 0.50                | 0.70  | 92    | 89 | 85 |
| p0                  | pa    | Power |    |    |
| (84% PPR n/arm=111) | Power |       |    |    |
| (74% PPR  n/arm=98) |       |       |    |    |  
13.4.2 A secondary HRQOL endpoint will be to determine whether patients treated with SBRT and sorafenib have an improved FACT-Hep score, as measured by the proportion of patients on each treatment arm with improvement, defined as an increase in the Trial Outcome Index (TOI) score of at least 7 points (minimally important difference), as compared to patients receiving sorafenib alone. The TOI scale consists of the physical well-being and functional well-being subscales from the FACT-G with hepatobiliary module. The power calculations, with the same assumptions, are the same as shown in Section 13.4.1.  
13.4.3 Another secondary HRQOL endpoint will be to determine whether patients treated with SBRT and sorafenib have an improved NCCN/FACT-Hep Symptom Index (FHSI-18) score, as measured by the proportion of patients on each treatment arm with improvement, defined as an increase of at least 2 points (minimally important difference), as compared to patients receiving sorafenib alone. The FHSI-18 has a total of 18 items assessing common symptoms when treating advanced hepatobiliary disease. The power calculations, with the same assumptions, are the same as shown in Section 13.4.1.
13.5 **Analysis Plan** (26-MAY-2022)
All analyses will be done based on the assigned treatment arm for all eligible patients entered.  
13.5.1 Statistical Methods Overall Survival Overall survival (OS) will be estimated by the Kaplan-Meier method (Kaplan 1958). The distribution of OS estimates between the 2 arms will be compared using the log rank test (Mantel 1966). OS time will be measured from the date of randomization to the date of death or last follow-up. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with OS. Progression-Free Survival Progression-free survival (PFS) will be estimated by the Kaplan-Meier method (Kaplan 1958). The distribution of PFS estimates between the 2 arms will be compared using the log rank test
(Mantel 1966). PFS time will be measured from the date of randomization to the date of first failure or last follow-up. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with PFS. Time-to-Progression (TTP)
Time-to-progression (TTP) will be estimated by the cumulative incidence method (Mantel 1966).  
The distribution of TTP estimates between the 2 arms will be compared using Gray's test (Gray 1988). TTP time will be measured from the date of randomization to the date of first failure or last follow-up. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with TTP.  
13.5.2 Interim Analysis to Monitor the Study Progress Interim reports will be prepared twice per year until the initial treatment results have been presented/published. In general, the interim reports will contain the following information:
- Patient accrual rate with a projected completion date (while the study is still accruing)
- Total patients accrued
- Distributions of important pretreatment and prognostic baseline variables
- The frequencies and severity of adverse events by treatment arm - Compliance rates of treatment delivery The interim reports will not contain the results from the treatment comparisons with respect to the primary endpoint, OS, or any secondary endpoints, with the exception of reporting of adverse events.  
13.5.3 CDUS Reports This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due January 31, April 30, July 31, and October 31.  
13.5.4 Significance Testing for Early Termination and/or Reporting Unacceptable Toxicity To address the safety of SBRT followed by sorafenib, the rate of unacceptable adverse events will be evaluated on both treatment arms. This analysis will focus on the following AEs occurring within 90 days from the start of protocol treatment definitely or probably related to protocol treatment: a) grade 4 or 5 hepatic b) grade 4 or 5 gastrointestinal c) grade 4 thrombocytopenia associated with any bleeding or grade 5 thrombocytopenia d) Any grade 5 treatment-related adverse event Assuming no more than a 10% rate of the above AEs on the sorafenib alone arm, the study chairs have determined that an increase to a rate of 30% or greater on the SBRT followed by sorafenib arm will be considered to be unacceptable. One-hundred and fifty-four patients provide 90% power to detect an increase in the rate of specified AEs from 10% to at least 30% with a 1sided alpha of 0.05, using a Chi-squared test for difference in proportions. If the p-value from the test described above is ≤ 0.05, the conclusion will be that the treatment-related unacceptable AE rate for the SBRT followed by sorafenib arm is at least 30% and accrual to the study will be stopped.
radiation therapy oncology group rtog
primary endpoint overall survival (os)

Three interim significance tests of treatment difference are planned. The timing of the interim analyses will be based on OS failure events, as described in Section 13.1.1. The maximum number of events required for the study is 238. Under the alternative hypothesis that the addition of SBRT will increase median OS from 10.5 months to 14.5 months, the projected numbers of events and the nominal significance levels for rejecting the H0 or the H1 for each of these two interim analyses are shown in the table below:  
| Efficacy:          |                       |           |           |
|--------------------|-----------------------|-----------|-----------|
| Interim Analysis   | Reject H0 if p(H0)  ≤ | Futility: |           |
| Reject H1 if Z(H0) | # Events (%)          |           |           |
| ≤                  |                       |           |           |
| #1                 | 0.001                 | 0         | 98 (41%)  |
| #2                 | 0.001                 | 0         | 143 (60%) |
| #3                 | 0.001                 | 0.385     | 190 (80%) |
radiation therapy oncology group rtog
nominal significance levels for interim

At each planned interim analysis, the p-value from the log-rank test assessing treatment efficacy and the Z-score assessing treatment futility with respect to OS will be compared to the nominal significance/critical levels in the table above. If the computed p-value is less than or equal to the nominal significance level boundary for rejecting the H0 (efficacy), then accrual to the trial will be stopped (if applicable), it will be concluded that the OS with SBRT and sorafenib (Arm 2) is significantly higher than sorafenib alone (Arm 1) and the results will be reported. If the Z-score is less than or equal to the nominal critical level boundary for rejecting the H1 (futility), then accrual to the trial will be stopped (if applicable) and it will be reported that it cannot be concluded that the OS with SBRT and sorafenib (Arm 2) is significantly higher than sorafenib alone (Arm 1).  
Otherwise, accrual to the trial or follow-up (as applicable) will continue until the next interim or final analysis.  
In addition to accrual, distributions of pretreatment characteristics, frequency and severity of adverse events, and compliance with protocol treatment, blinded efficacy results will be reported to the NRG Oncology data monitoring committee (DMC), following the required number of events for each planned interim analysis.  
13.5.5 Analysis for Endpoints Related to HRQOL
Distributions of QOL data collection patterns over all collection points in each treatment arm will be described. To inspect the missing data mechanism for each tool, at least a graphical method will be used. A missing completely at random (MCAR) mechanism exists when missing values are randomly distributed across all observations. A missing at random (MAR) mechanism exists when values are not randomly distributed across all observations, rather than one or more subsamples.  
If the missing data is MCAR, listwise deletion (complete case analysis) will be done. If the MAR assumption is supported by the data, then an imputation method such as multiple imputation will be applied to impute missing data. If the MAR assumption is not supported by the data, then adjusting for covariates (such as the baseline QOL score) might reduce the conditional association between outcomes and missing values. If missing data patterns look similar when stratified by such covariate(s), then an analysis that adjusts for such covariate(s) will be conducted and an imputation method such as multiple imputation will be applied. If approximate conditional independence cannot be obtained with any set of covariates, then MNAR (missing not at random) must be addressed by an explicit model for the missing data mechanism (Donaldson 2005) and then an imputation method such as multiple imputation will be applied. All results from the imputed analysis using the multiple imputation will be compared to the complete case analysis results to assess any potential biases. FACT-Hep Scoring and Analysis The FACT-Hep will be scored per the FACT-Hep Scoring Guidelines (Version 4 **www.facit.org**),
with higher scores indicating better QOL.  
The primary objective in the HRQOL analysis is improvement in the FACT-Hep score, defined as an increase of 5 points or more from baseline to the assessment at 6 months from the start of protocol therapy. Chi-squared tests will be used to test the null hypothesis that the proportion of patients categorized as "improved" will be the same for the 2 treatment arms, versus the alternative hypothesis that the proportion of patients categorized as "improved" is higher for the SBRT+sorafenib arm. Improvement in the FACT-Hep score, as defined above, will also be compared between the treatment arms for changes from baseline to both 3 and 12 months with the same methodology as listed above.  
Correlation of baseline FACT-Hep and survival will be evaluated.
radiation therapy oncology group rtog
eq-5d scoring and analysis

The quality-adjusted survival of each treatment will be evaluated and compared using EQ-5D if the primary endpoint supports the primary hypothesis.  
The EQ-5D is a 2-part self-assessment questionnaire. The first part consists of 5 items covering 5 dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is measured by a 3-point likert scale (1-no problems, 2-moderate problems, and 3extreme problems). The second part is a visual analog scale (VAS) valuing the current health state measured by a 100-point scale with a 10-point interval (0-worst imaginable health state, 100-best imaginable health state). We will transform the 5-item index score and VAS score into a utility score between 0 (worst health state) and 1 (best health state) for comparative purposes.  
Patients will complete the EQ-5D at the following time points: pretreatment (baseline), 3 months, 6 months, and 12 months post initiation of protocol therapy.  
To examine trade-offs between the survival time and QOL, they will be combined for each patient into a single measurement: quality-adjusted life years (QALY). If (and only if) the primary endpoint hypothesis is substantiated, a quality-adjusted survival analysis will be conducted. The qualityadjusted survival analysis will not be done until after the primary endpoint results are published. QALY is defined by the weighted sum of different time episodes added up to a total qualityadjusted survival time. QALY will be analyzed at 2 time points: at 6 and 12 months from start of treatment, using the EQ-5D.  
13.5.6 Analysis for Reporting the Initial Treatment Results The primary hypothesis of this study is SBRT and sorafenib will increase the median OS from 10.5 months to 14.5 months as compared to sorafenib alone for patients with hepatobiliary carcinoma. The timing of initial treatment results analysis will be as described in Section 13.5.7 and will include:
- Tabulation of all cases entered and those excluded from the analyses with the reasons for exclusion given
- Distributions of important prognostic baseline variables
- The frequencies and severity of adverse events by treatment arm.  
- Compliance rate of treatment delivery
- Observed results with respect to the primary and secondary endpoints All eligible patients randomized will be included in the comparison and will be grouped by assigned treatment in the analysis. The primary hypothesis of treatment benefit will be tested using the log-rank statistic with a significance level of 0.05, given that the 3 interim analyses were carried out per Section 13.5.4. Additional analyses of treatment effect will be performed using the Cox proportional hazard model with the stratification factor included as a fixed covariate, as well as any factors that show an imbalance between the arms (eg, age, gender, race, Zubrod status, etc.).  
13.5.7 Time-Driven Definitive Analysis The statistical analysis plan changes were done in accordance with the NCI Policy for Major Design Amendments for Ongoing Randomized Clinical Trials. The specifics for the changes were performed by a statistician independent from the trial.  
External circumstances have resulted in accrual closure with 177 eligible patients currently enrolled. Due to the limited sample size and observed event rate, coupled with concerns regarding adoption of new therapy among participants, the trial primary endpoint will be reported at a fixed calendar date (July 1, 2022, or completion of this amendment, whichever is later). The targeted treatment effect (experimental/control HR = 0.72) and alpha level (one-sided 0.05) will remain unchanged from the original design.  
The primary endpoint analysis will thus be performed with the number of OS events reported through July 1, 2022 (or completion of this amendment, whichever is later). It is anticipated that at that time, at least 155 OS event will have been observed. The log-rank test with 155 OS events will have 65% power at one-sided alpha 0.05 to detect the targeted treatment effect (experimental/control HR of 0.72).  
13.6 Gender and **Minorities** (23-SEP-2022)
Both men and women of all races and ethnic groups are eligible for this study. In conformance with the national Institutes of Health (NIH) Revitalization Act of 1993 with regard to inclusion of women and minorities in clinical research, possible interaction between race/ethnicity and treatment has been considered. It is projected that 80% of the patients will be men and 20%
women; 2% will be of Hispanic or Latino ethnicity and 98% will not; racial distribution will be 73% white, 2% black or African American, and 25% Asian. Assuming no differences between the ethnicities, or among the races, the statistical power for detecting the hypothesized treatment difference is 64% for males and 21% for females. Assuming no differences between genders or the ethnicities, the statistical power is 60% for whites and 25% for Asians. The projected nonWhite/Asian accrual rate is too low for any meaningful treatment comparisons. Assuming no differences between the genders, or among the races, the statistical power for detecting the hypothesized treatment difference in non-Hispanic/Latino ethnicity will be 73%. The projected Hispanic/Latino accrual rate is too low for any meaningful treatment comparisons.  
The following table lists the projected accrual by gender, ethnic, and racial categories.  
| DOMESTIC                                   | Ethnic Categories      |                    |       |    |     |
|--------------------------------------------|------------------------|--------------------|-------|----|-----|
| Racial Categories                          | Not Hispanic or Latino | Hispanic or Latino | Total |    |     |
| Female                                     | Male                   | Female             | Male  |    |     |
| American Indian or Alaska                  | 0                      | 1                  | 0     | 1  | 2   |
| Native Asian                               | 1                      | 4                  | 0     | 3  | 8   |
| Native Hawaiian or other                   | 1                      | 0                  | 0     | 0  | 1   |
| Pacific Islander Black or African American | 3                      | 8                  | 1     | 2  | 14  |
| White                                      | 10                     | 52                 | 3     | 9  | 74  |
| More than one race                         | 0                      | 1                  | 0     | 2  | 3   |
| TOTAL                                      | 15                     | 66                 | 4     | 17 | 102 |  
| Ethnic Categories                          |                    |       |        |      |     |
|--------------------------------------------|--------------------|-------|--------|------|-----|
| Not Hispanic or Latino                     | Hispanic or Latino | Total |        |      |     |
| Racial Categories                          | Female             | Male  | Female | Male |     |
| American Indian or Alaska                  | 0                  | 0     | 0      | 0    | 0   |
| Native Asian                               | 9                  | 41    | 0      | 0    | 50  |
| Native Hawaiian or other                   | 0                  | 0     | 0      | 0    | 0   |
| Pacific Islander Black or African American | 1                  | 5     | 0      | 0    | 6   |
| White                                      | 24                 | 110   | 0      | 0    | 134 |
| More than one race                         | 0                  | 0     | 0      | 0    | 0   |
| TOTAL                                      | 34                 | 156   | 0      | 0    | 190 |
radiation therapy oncology group rtog
references (27oct2017)

Ben-Josef E, Normolle D, Ensminger WD, et al. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol. 23:8739-8747, 2005.  
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APPENDIX I  
STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS **(13-MAY-2019)**  
| STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (13-MAY-2019)                                                                                     |                    |                  |                  |
|----------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|------------------|------------------|
| Pre-Treatment Assessments                                                                                                                          | ≤360 days prior to | 28 days prior to | 14 days prior to |
| (may be required for eligibility)                                                                                                                  | study entry        | study entry      |                  |
| study entry                                                                                                                                        |                    |                  |                  |
| Biopsy, cytology ,radiographically                                                                                                                 | X                  |                  |                  |
| confirmed HCC History/physical*                                                                                                                    | X                  |                  |                  |
| Performance status                                                                                                                                 | X                  | X                |                  |
| TNM stage, BCLC stage Child Pugh score, MELD score                                                                                                 | X^                 |                  |                  |
| Assessment by radiation  oncologist, medical oncologist or  hepatologist                                                                           | X                  | X                |                  |
| CBC w/diff, ANC, platelets  Serum creatinine or creatinine                                                                                         | X                  |                  |                  |
| clearance, ALT, AST Alpha-fetoprotein                                                                                                              | X                  |                  |                  |
| Bilirubin, albumin, INR, ALP,  phosphate, sodium, potassium,  chloride, magnesium                                                                  | X                  |                  |                  |
| Calcium                                                                                                                                            | X                  |                  |                  |
| bHCG test (if applicable)                                                                                                                          | X                  |                  |                  |
| Multi-phasic liver CT or multiphasic liver MRI                                                                                                                                                    | X                  |                  |                  |
| CT chest and CT or MR abdomen and CT or MR pelvis, or PET CT  chest/abdomen/pelvis                                                                 | X                  |                  |                  |
| Quality of Life (for consenting                                                                                                                    | Pre-Treatment      |                  |                  |
| patients) Tissue banking (for consenting                                                                                                           | Pre-Treatment      |                  |                  |
| patients) Plasma banking (for consenting                                                                                                           | Pre-Treatment      |                  |                  |
| patients) Whole blood banking (for                                                                                                                 | Pre-Treatment      |                  |                  |
| consenting patients) Informed consent                                                                                                              | X                  |                  |                  |
| *Including ascites, encephalopathy, weight, height, and blood pressure. ^ INR < 28 days can be used for scoring < 14 days -Continued on next page- |                    |                  |                  |  
| APPENDIX I                                                                                                                                                                                                                                                                                                                                                                                                                            |                                             |             |    |    |    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------|-------------|----|----|----|
| STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT AND FOLLOW-UP (25-MAR-2020)  Assessments SBRT During Sorafenib (Arm 1 and 2) Follow up for ALL  Patients**  (Arm 1 and 2) Arm 2 - Weekly  (following  at least  one  fraction) Arm 2 - Prior to  starting  sorafenib,  post last  SBRT  fraction Monthly (or per local standard  of care) Every 3  months from study  entry for 2  years from  study entry Then,  every 6  months |                                             |             |    |    |    |
| History/physical*                                                                                                                                                                                                                                                                                                                                                                                                                     | X                                           | X           | X  | X  | X  |
| Performance status                                                                                                                                                                                                                                                                                                                                                                                                                    | X                                           | X           | X  | X  | X  |
| Child Pugh score,                                                                                                                                                                                                                                                                                                                                                                                                                     | X                                           | X           |    |    |    |
| MELD score Assessment by  radiation oncologist,  medical oncologist  or hepatologist                                                                                                                                                                                                                                                                                                                                                  | X                                           | X           | X  | X  | X  |
| Assessment by  medical oncologist  and/or hepatologist                                                                                                                                                                                                                                                                                                                                                                                | X                                           | X           |    |    |    |
| CBC w/diff, ANC,                                                                                                                                                                                                                                                                                                                                                                                                                      | X                                           | X           | X  | X  |    |
| platelets  Serum creatinine or  creatinine  clearance, ALT,  AST                                                                                                                                                                                                                                                                                                                                                                      | X                                           | X           | X  | X  |    |
| Bilirubin, albumin,  INR, ALP,  phosphate, sodium,  potassium, chloride,  magnesium                                                                                                                                                                                                                                                                                                                                                   | X                                           | X           |    |    |    |
| Calcium                                                                                                                                                                                                                                                                                                                                                                                                                               | X                                           |             |    |    |    |
| Alpha-fetoprotein                                                                                                                                                                                                                                                                                                                                                                                                                     | X                                           | X           |    |    |    |
| Multi-phasic liver  CT or multi-phasic  liver MRI                                                                                                                                                                                                                                                                                                                                                                                     | X (for 2  years then  every 6  months)      | X           |    |    |    |
| CT chest                                                                                                                                                                                                                                                                                                                                                                                                                              | X (annually                                 | X (annually |    |    |    |
| only)                                                                                                                                                                                                                                                                                                                                                                                                                                 | only)                                       |             |    |    |    |
| 77                                                                                                                                                                                                                                                                                                                                                                                                                                    | RTOG 1112, Version Date: September 23, 2022 |             |    |    |    |  
| Adverse event eval  (and as needed  based on reporting  requirements)†                                                                                                                                                                                                                                                                       | X                                            | X   | X   | X   | X   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------|-----|-----|-----|-----|
| Quality of Life (for  consenting patients)                                                                                                                                                                                                                                                                                                   | 3, 6, 12  months  only                       |     |     |     |     |
| Plasma and whole  blood banking (for  consenting  patients)                                                                                                                                                                                                                                                                                  | 1 and 3  months  only (see  section  10.2.6) |     |     |     |     |
| Pill diary (do not send                                                                                                                                                                                                                                                                                                                      | Daily during sorafenib                       |     |     |     |     |
| to NRG HQ) *Including ascites, encephalopathy, weight, and blood pressure. ** Including patients receiving sorafenib or patients who have discontinued sorafenib. † Including skin toxicity (in and out of RT volumes for SBRT arm). Note: For q monthly tests, +/- 2 week is permitted, and for q 3, 6 and 12 monthly tests, +/- 3 weeks is |                                              |     |     |     |     |  
*Including ascites, encephalopathy, weight, and blood pressure.  
** Including patients receiving sorafenib or patients who have discontinued sorafenib. † Including skin toxicity (in and out of RT volumes for SBRT arm). Note: For q monthly tests, +/- 2 week is permitted, and for q 3, 6 and 12 monthly tests, +/- 3 weeks is permitted. Pill diary: *http://www.rtog.org/ClinicalTrials/NonStudySpecificForms.aspx* After patients have been documented to have radiologic PD, the above follow-up is recommended, but not mandatory.
radiation therapy oncology group rtog
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
appendix iii ajcc staging system
appendix ii zubrod performance scale

Edge SB, ed. AJCC Cancer Staging Manual 7th ed. New York, NY, 2010
appendix iii ajcc staging system
hepatocellular carcinoma primary tumor (t)

TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Solitary tumor without vascular invasion T2 Solitary tumor with vascular invasion or Multiple tumors no more than 5 cm T3a Multiple tumors more than 5cm T3b Tumor involving a major branch of the portal or hepatic vein(s)
T4 Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum
appendix iii ajcc staging system
regional lymph nodes (n)

NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Regional lymph node metastases
appendix iii ajcc staging system
distant metastases (m)

MX Distant metastases cannot be assessed M0 No distant metastases M1 Distant metastases
appendix iii ajcc staging system
stage grouping

Stage I T1 N0 M0 Stage II T2 N0 M0  
Stage IIIA T3a N0 M0  
Stage IIIB T3b N0 M0  
Stage IIIC T4 N0 M0 Stage IVA Any T N1 M0  
Stage IVB Any T Any N M1
appendix iii ajcc staging system
appendix v (27oct2017) multi-phase hepatocellular

Multi-phase liver CT protocol using iodinated intravenous (IV) contrast will be obtained at 2.5 or 3 mm slice thickness. The four phase HCC protocol includes a non-contrast CT, arterial (A) phase imaging, portal venous
(V) phase imaging and delayed (D) phase imaging. The A phase of imaging demonstrates hypervascularity of HCC. The V phase is often best for visualization of vascular thrombi. The D phase imaging demonstrates washout of HCC. All four phases are recommended for use at baseline diagnosis for HCC; A/V/D phase imaging is recommended for follow-up of HCC patients, with all phases including the whole liver and V or D phase including the entire abdomen. For CT simulation, at least 2 phases of imaging are recommended (A/V or A/D),
with all phases including the whole liver and one phase including enough of the abdomen to develop a patient model for radiation planning. All multi-phase imaging is recommended to be obtained in breath hold, with the arms up when possible.
appendix iii ajcc staging system
the timing of imaging after

The timing varies between 16 and 64 detector scanners (with image acquisition occurring faster on a 64 detector CT scanner). It is recommended that IV contrast (e,g. Visipaque) 2cc/kg to a max of 180cc be injected @ 5cc/second using a minimum of 20G antecubital. IV bolus tracking, a commercially available technique, is recommended for use to control for variations in cardiac circulation time, to ensure the images are obtained during the correct phases of contrast enhancement. As is standard practice, a cursor is placed in the aorta at the level of the origin of the celiac axis and is used to detect when contrast arrives in the abdominal aorta and raises the attenuation value to 100 Hounsfield Units. For a 64 detector scanner, A, V and D phase scanning occurs 20, 60 and 180 seconds, respectively, after the 100HU threshold is reached.
appendix iii ajcc staging system
mr imaging

Gadolinium or Primovist/Eovist (Gd-EOB-DTPA) enhanced liver MRI may be utilized to facilitate target delineation and should be used if there is a contraindication to IV CT contrast. It is recommended that non-contrastenhanced and dynamically obtained T1 weighted sequences at a slice thickness of 7mm at maximum be used.  
Details of the imaging protocol should be developed in collaboration with the diagnostic radiology department.  
If a patient has contraindications to CT and MR IV contrast, then non-contrast T1 weighted MR images may be used for target delineation, only if T1 weighted images demonstrate the HCC with clearly defined edges.
appendix vi (27oct2017) child pugh
mr imaging

| Clinical and Biochemical Parameters                                                                                                                                                                                                                      | Score (Points) for Increasing Abnormality   |      |        |          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------|------|--------|----------|
|                                                                                                                                                                                                                                                          | 1                                           | 2    | 3      |          |
| Encephalopathy                                                                                                                                                                                                                                           |                                             | None | 1 - 2  | 3 - 4    |
| Ascites                                                                                                                                                                                                                                                  |                                             | None | Slight | Moderate |
| Non clinical trace ascites on imaging only is not mandated to be included as "mild ascites" (2 points). Instead it may receive 1 point on this study.  Albumin (g/dL) > 3.5 2.8 - 3.5 < 2.8 INR* < 1.7 1.7 - 2.3 > 2.3 Bilirubin (mg/dL) 1 - 2 2 - 3 > 3 |                                             |      |        |          |  
Class A 5 - 6 points Class B 7 - 9 points Class C 10 - 15 points  
Alternative Biochemical Units Score (Points) for Increasing Abnormality  
1 2 3 Albumin (g/L) > 35 28- 35 < 28 Bilirubin (umol/L) 0-34.2 34.3 - 51.3 > 51.3  
Reference: Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma exchange blood transfusion. N Engl J Med 1966; 274 (9): 473-481  
|         | Stages of Hepatic Encephalopathy                                         |
|---------|--------------------------------------------------------------------------|
| Stage 1 | Euphoria or depression, mild confusion, slurred speech, disordered sleep |
| Stage 3 | Marked confusion, incoherent speech, sleeping but arousable              |
appendix vi (27oct2017) child pugh
appendix vii model for end-stage

The MELD score is based on the patient's bilirubin, creatinine and the INR to predict survival. It is calculated according to the following formula:
MELD = 9.57 * ln(serum creatinine in mg/dl) + 3.78 * ln(total serum bilirubin in mg/dl) + 11.2 * ln(INR) + 6.43 If any value is less than one, it should be given a value of 1. Reference; Kamath PS, Kim WR (March 2007). "The model for end-stage liver disease (MELD)". Hepatology 45 (3): 797–805.
appendix vi (27oct2017) child pugh
appendix viii (8/26/14) veff calculation

Use of effective liver volume (Veff) to aid in dose prescription is permitted if available, but it is not to be the primary tool used for dose allocation. The following table is used as a guide. If there are discrepancies in the Veff and mean liver dose (MLD) for the prescription dose allocation, MLD will be used for dose allocation. A call to the clinical PI or physics PI is recommended if this occurs.  
| Liver Veff   | Planned Prescription   | If the allowed Veff is exceeded at this   |
|--------------|------------------------|-------------------------------------------|
| Dose (Gy)    | planned dose           |                                           |
| < 25%        | 50                     | Reduce to 45 Gy and re-evaluate           |
| 25 - 29%     | 45                     | Reduce to 40 Gy and re-evaluate           |
| 30 - 34%     | 40                     | Reduce to 35 Gy and re-evaluate           |
| 35 - 44%     | 35                     | Reduce to 30 Gy and re-evaluate           |
| 45 - 54%     | 30                     | Reduce to 27.5 Gy and re-evaluate         |
| 55 - 64%     | 27.5                   | Ineligible                                |  
Veff must be calculated using the methods described in the references below. The equation below may be used.  
  
where ∆vi is a volume bin of a differential DVH, di is the dose to that volume, and dref is the reference dose and n is the volume effect parameter (equal to 0.97 in this application).. The prescription dose is used as the reference dose in this study.  
1. Kutcher GJ BC, Brewster L et al. Histogram reduction method for calculating complication probabilities for threedimensional treatment planning evaluations. Int J Radiat Oncol, Biol, Phys 1991;21:137-146.  
2. Dawson LA, Eccles C, Craig T. Individualized Image Guided Iso-NTCP based Liver Cancer SBRT. Acta Oncol. 45:
856 - 864, 2006.
appendix ix (27oct2017) appendices for
shipping instructions

U.S. Postal Service Mailing Address: For non-urgent FFPE or Non-frozen Specimens Only NRG Oncology **Biospecimen Bank**
University of California San Francisco - Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143 Courier Address (FedEx, UPS, etc.): For Frozen or Trackable Specimens NRG Oncology Biospecimen Bank University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 Include all NRG Oncology paperwork in pocket of biohazard bag.  
Check that the Specimen Transmittal Form (ST) has the consent boxes checked off. Check that all samples are labeled with the NRG Oncology 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 FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap blocks with bubble wrap. Place padding in top of container so that if you shake the container the blocks are not shaking. If you can hear the slides 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.  
**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 NRG Oncology **Biospecimen Bank**
by e-mail: NRGBB@ucsf.edu or phone: 415-476- 7864 or Fax: 415-476-5271.
appendix ix (27oct2017)
shipping instructions

NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS
This Kit is for collection, processing, storage, and shipping of serum, plasma or whole blood (as specified by the protocol):
- Kit contents (Note: Sites are responsible for providing **blood draw tubes):**
- Thirty (30) 1 ml cryovials for plasma and serum - all time points
- Three (3) 2 ml cryovials for whole blood
- Biohazard bags (7) and Absorbent shipping material (7)
- One Styrofoam container (inner) and Cardboard shipping (outer) box per case - UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers - Specimen Transmittal Form (ST) and Kit Instructions
appendix ix (27oct2017)
process

1. Allow one red top tube to clot for 30 minutes at room temperature.  
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4°C (preferred). If sites are unable to process samples at 4°C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the ST.  
3. Aliquot a minimum of 0.5 ml serum into each of the five cryovials as necessary for the serum collected, labeled with study and case numbers, collection date, protocol time-point collected (e.g.  
pretreatment, post-treatment), and clearly mark specimen as "serum".  
4. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90° C, and store frozen until ready to ship. See below for storage conditions.  
5. Store serum at -70 to -90° C until ready to ship on dry ice. See below for storage conditions.
appendix ix (27oct2017)
process

1. After collection, 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 4°C (preferred). If sites are unable to process samples at 4°C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the ST.  
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 a minimum of 0.5 ml plasma into each of the five cryovials as necessary for the plasma collected, labeled with study and case numbers, collection date, time point collected and clearly mark specimen as "plasma". Avoid pipetting up the buffy coat layer.  
5. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90°C.  
6. Store frozen plasma until ready to ship on dry ice. 7. See below for storage conditions.
appendix ix (27oct2017)
(c) whole blood for dna

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 1.0-2.0 ml blood into three 2ml cryovials as necessary for the blood collected, labeled with study and case numbers, collection date, time point collected and clearly mark specimen as "blood".  
3. Place cryovials into biohazard bag and freeze tubes upright immediately at -70 to -80° Celsius.  
4. Store blood samples frozen until ready to batch ship on dry ice. 5. See below for storage conditions.
appendix ix (27oct2017)
please make sure that every

Freeze Blood samples in a -80°C Freezer or on Dry Ice or snap freeze in liquid nitrogen.  
Store at -80°C (-70°C to -90°C) until ready to ship.  
If a -80°C Freezer is not available, Samples can be stored short term in a -20°C 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.  
(continued on next page)
appendix ix (27oct2017)
blood collection kit instructions (continued)

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 NRG Oncology 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**
NRGBB@ucsf.edu or call (415)476-7864.
appendix ix (27oct2017)
shipping address

Courier Address (FedEx, UPS, etc.): For all Frozen Specimens NRG Oncology Biospecimen Bank - San Francisco University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 For questions, call 415-476- 7864 or e-mail: NRGBB@ucsf.edu
appendix x
vascular thrombosis stratification diagram

One stratification factor is degree of vascular thrombosis.  The three strata are:
1) Tumor thrombosis involving the IVC, the main portal vein or the right or left main branch portal vein. This includes any thrombi involving these vascular structures at least partially, defined as involving any of the IVC, main portal vein or the right or left main branches of the portal vein.  The right and left main branches of the portal vein are the first branches off the main portal vein, up to the first bifurcation of the right and left portal veins, as shown in the diagram below.  
2) Any other thrombosis (e.g. involving the more distal portal veins or hepatic veins)
3) No vascular thrombosis.