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appendix a performance status criteria

| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                   |                                                                           |                                                                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|---------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                                                      | Descriptions                                                  | Percent                                                                   | Description                                                            |
| 100                                                                                                                                                                                        | Normal, no complaints, no evidence  of disease.               |                                                                           |                                                                        |
| Normal activity. Fully active, able                                                                                                                                                        |                                                               |                                                                           |                                                                        |
| 0                                                                                                                                                                                          | to carry on all pre-disease  performance without restriction. | 90                                                                        | Able to carry on normal activity;  minor signs or symptoms of disease. |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). | 80                                                            | Normal activity with effort; some  signs or symptoms of disease.          |                                                                        |
| 1                                                                                                                                                                                          | 70                                                            | Cares for self, unable to carry on  normal activity or to do active work. |                                                                        |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                             | Requires occasional assistance, but                           |                                                                           |                                                                        |
| 60                                                                                                                                                                                         | is able to care for most of his/her  needs.                   |                                                                           |                                                                        |
| 2                                                                                                                                                                                          | 50                                                            | Requires considerable assistance and  frequent medical care.              |                                                                        |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                     | 40                                                            | Disabled, requires special care and  assistance.                          |                                                                        |
| 3                                                                                                                                                                                          | 30                                                            | Severely disabled, hospitalization  indicated. Death not imminent.        |                                                                        |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                            | Very sick, hospitalization indicated.  Death not imminent.                |                                                                        |
| 4                                                                                                                                                                                          | 10                                                            | Moribund, fatal processes  progressing rapidly.                           |                                                                        |
| 5                                                                                                                                                                                          | Dead.                                                         | 0                                                                         | Dead.                                                                  |
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appendix b

New York Heart Association Classifications Clinical Evaluation of Functional Capacity of Patients with Heart Disease in Relation to Ordinary Physical Activity  
| Need for      | Physical Ability                                                      |             |                     |                    |             |
|---------------|-----------------------------------------------------------------------|-------------|---------------------|--------------------|-------------|
| Class         | Cardiac Symptoms                                                      | Limitations | Additional Rest*    |                    | to work**__ |
| I             | None                                                                  | None        | None                | Full time          |             |
| II            | Only moderate                                                         | Slight      | Usually only slight | Usually full       |             |
| or occasional | time                                                                  |             |                     |                    |             |
| III           | Defined, with  less than  ordinary activity                           | Marked      | Usually moderate    | Usually part  time |             |
| IV            | May be present  even at rest,  and any activity  increases discomfort | Extreme     | Marked              | Unable to work     |             |  
* To control or relieve symptoms, as determined by the patient, rather than as advised by the physician.  
** At accustomed occupation or usual tasks.  
Reference: Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956.  
(Modified from New York Heart Association, 1953).
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appendix c medications that may

The following table presents a list of drugs that may prolong the QTc. These drugs are prohibited during the study. AZD 6244 may be administered after a 5 half-life washout period elapses following the use of these drugs. Washout period is based on roughly 5 half-lives and rounded to a convenient interval.  
| drugs. Washout period is based on roughly 5 half-lives and rounded to a convenient interval.   | Possible  Washout                                                                                          |                         |
|------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------|-------------------------|
| Period - Days                                                                                  |                                                                                                            |                         |
| Alfuzocin                                                                                      | ~10 hours                                                                                                  | 7                       |
| Amantadine                                                                                     | 17 +/- 4 hours (10-25)                                                                                     | 4                       |
| Amiodarone (cordarone)                                                                         | 58 days (15-142)                                                                                           | 180                     |
| 36 days (active metabolite)                                                                    | Possible                                                                                                   |                         |
| Compound                                                                                       | Compound Half Life                                                                                         | Washout Period  - Hours |
| Amitriptyline*                                                                                 | > 24 hours, wide interpatient variability                                                                  |                         |
| Arsenic trioxide                                                                               | Not characterized                                                                                          |                         |
| Azithromycin                                                                                   | 40 hours                                                                                                   |                         |
| Bepridil                                                                                       | 42 hr (26-64)                                                                                              | 10                      |
| Chloral hydrate                                                                                | Readily converted to Trichloroethanol (active                                                              | 48                      |
| metabolite T1/2=7-10 hour)                                                                     |                                                                                                            |                         |
| Chloroquine                                                                                    | Prolonged (days to weeks)                                                                                  |                         |
| Chlorpromazine                                                                                 | 30 +/- 7 hours                                                                                             | 7                       |
| Cisapride                                                                                      | 6 - 12 hour, up to 20 hour                                                                                 | 60                      |
| Clarithromycin                                                                                 | Non linear PK3-4 hr (250mg Q12)                                                                            | 36                      |
| 5-7 hr (500mg Q12)                                                                             |                                                                                                            |                         |
| Cloroquine                                                                                     | 6 to 60 days; mean 20 days                                                                                 |                         |
| Desipramine*                                                                                   | > 24 hours, wide interpatient variability                                                                  |                         |
| Disopyramide                                                                                   | 6.7 hr (4-10)                                                                                              | 36                      |
| Dofetilide                                                                                     | 10 hr                                                                                                      | 48                      |
| Dolesetron                                                                                     | 8.1 hr                                                                                                     |                         |
| Domperidone                                                                                    | 7-8 hr                                                                                                     | 48                      |
| Doxepin*                                                                                       | > 24 hours, wide interpatient variability                                                                  |                         |
| Droperidol                                                                                     | 2.2 hours                                                                                                  | 10                      |
| Erythromycin                                                                                   | * Each salt form has different Half life*                                                                  |                         |
| Felbamate                                                                                      | 20-23 hr                                                                                                   | 5                       |
| Flecainide                                                                                     | 20 hr (12-27)                                                                                              | 5                       |
| Foscarnet                                                                                      | 87.5+/-41.8 hours                                                                                          | 20                      |
| *distribution and release from bone*                                                           |                                                                                                            |                         |
| Fosphenytoin                                                                                   | 12-29 hr                                                                                                   | 6                       |
| Gatifloxacin                                                                                   | 7-14 hr                                                                                                    | 48                      |
| Gemifloxacin                                                                                   | 7 hours                                                                                                    | 48                      |
| Grepafloxacin                                                                                  | 16 hr                                                                                                      | 3                       |
| Halofantrine                                                                                   | 6-10 days ( variable among individual)                                                                     | 45                      |
| Haloperidol                                                                                    | 18 +/-5 hr                                                                                                 | 5                       |
| Ibutilide                                                                                      | 6 hours (2-12) * variable among subject*                                                                   | 36                      |
| Imipramine*                                                                                    | > 24 hours, wide interpatient variability                                                                  |                         |
| Indapamide                                                                                     | 14 hours (biphasic elimination)                                                                            | 3                       |
| Isradipine                                                                                     | 8 hours ( multiple metabolites)                                                                            | 48                      |
| Levofloxacin                                                                                   | 6-8 hours                                                                                                  | 48                      |
| Levomethadyl                                                                                   | Multiple compartment PK with active metabolite 2.6 day for LAAM, 2 day for nor-LAAM, 4 day  for dinor-LAAM | 20                      |
| Lithium                                                                                        | 24 hour (10-50)                                                                                            | 7                       |  
| Possible Washout                                                                                                               | Possible                                                                                                                              |                |         |
|--------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------|----------------|---------|
| Compound                                                                                                                       | Compound Half Life                                                                                                                    | Period - Hours | Washout |
| Period - Days                                                                                                                  |                                                                                                                                       |                |         |
| Mesoridazine                                                                                                                   | 24-48 hours ( animal study)                                                                                                           | 10             |         |
| Methadone                                                                                                                      | 15-30 hours                                                                                                                           | 7              |         |
| Moexipril/HCTZ                                                                                                                 | 2-9 hour (include active metabolite) for                                                                                              | 48             |         |
| moexipril; 5.6-14.8 hours for HCTZ                                                                                             |                                                                                                                                       |                |         |
| Moxifloxacin                                                                                                                   | 12 +/-1.3 hours                                                                                                                       | 72             |         |
| Naratriptan                                                                                                                    | 6 hours                                                                                                                               | 36             |         |
| Nicardipine                                                                                                                    | ~ 2 hour post IV infusion                                                                                                             | 12             |         |
| Nortriptyline*                                                                                                                 | > 24 hours, wide interpatient variability                                                                                             |                |         |
| Octreotide                                                                                                                     | 1.7 hours                                                                                                                             | 12             |         |
| Ofloxacin                                                                                                                      | 5 to 7.5 hours                                                                                                                        | 2              |         |
| Ondansetron                                                                                                                    | 4 hours (IV/IM); 3 hours (PO)                                                                                                         | 1 to 3         |         |
| Pentamidine                                                                                                                    | 6.4+/-1.3 hours                                                                                                                       | 36             |         |
| Pimozide                                                                                                                       | 55 hours                                                                                                                              | 10             |         |
| Procainamide                                                                                                                   | 3-4 hour for PA and NAPA (active metabolite)                                                                                          | 24             |         |
| Protiptyline*                                                                                                                  | > 24 hours, wide interpatient variability                                                                                             |                |         |
| Quetiapine                                                                                                                     | 6 hours                                                                                                                               | 36             |         |
| Quinidine                                                                                                                      | 6-8 hours in adult; 3-4 hours in children                                                                                             | 36             |         |
| Quinine                                                                                                                        | 4-5 hours                                                                                                                             |                |         |
| Risperidone                                                                                                                    | 3-20 hours (extensive to poor metabolizer) 9-hydroxyrisperidone (active metabolite) T ½  =21-30 hours (extensive to poor metabolizer) | 4              |         |
| Salmeterol                                                                                                                     | 5.5 hours ( only one datum)                                                                                                           | 36             |         |
| Sotalol                                                                                                                        | 12 hours                                                                                                                              | 72             |         |
| Sparfloxacin                                                                                                                   | 20 hours (16-30)                                                                                                                      | 4              |         |
| Sumatriptan                                                                                                                    | 2.5 hours                                                                                                                             | 12             |         |
| Tacrolimus                                                                                                                     | ~34 hours in healthy; ~19 hours in Kidney                                                                                             | 7              |         |
| transplant                                                                                                                     |                                                                                                                                       |                |         |
| Tamoxifen                                                                                                                      | 5-7 days (biphasic)                                                                                                                   | 30             |         |
| Telithromycin                                                                                                                  | 2-3 hr                                                                                                                                | 24             |         |
| Thioridazine                                                                                                                   | 20-40 hours (Phenothiazines)                                                                                                          | 7              |         |
| Tizanidine                                                                                                                     | 2.5 hours                                                                                                                             | 12             |         |
| Vardenifil                                                                                                                     | 4 to 5 hours                                                                                                                          |                |         |
| Venlaflaxine                                                                                                                   | 5 +/-2 hours for parent comp.                                                                                                         | 60             |         |
| 11+-2 hours for OVD (active metabolite)                                                                                        |                                                                                                                                       |                |         |
| Voriconizole                                                                                                                   | 6 hours; dose dependent                                                                                                               |                |         |
| Ziprasidone                                                                                                                    | 7 hr                                                                                                                                  | 36             |         |
| Zolmitriptan                                                                                                                   | 2.8-3.7 hours (higher in female)                                                                                                      | 18             |         |
| * Weakly associated with Torsades de Pointes and/or QT prolongation but that are unlikely to be a risk for Torsades de Pointes |                                                                                                                                       |                |         |  
* Weakly associated with Torsades de Pointes and/or QT prolongation but that are unlikely to be a risk for Torsades de Pointes when used in usual recommended dosages and in patients without other risk factors (e.g., concomitant QT prolonging drugs, bradycardia, electrolyte disturbances, congenital long QT syndrome, concomitant drugs that inhibit metabolism).
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references 1. physician's desk reference

2. **Facts and Comparisons ( update to June 2005)** 3. The Pharmacological Basis of Therapeutics 9th Edition, 1996 APPENDIX D: Patient's Medication Diary Patient name_____________________________ Page 1 of 2
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instructions to the patient

1. Complete this form for both AZD6244 and Capecitabine.  
2. You must take AZD6244 on an empty stomach with water only, either 1 hour before or two hour after meals. Capecitabine should be taken two hours before radiation with food.  
3. Record the date, the number of pills you took, and when you took them. 4. If you have any comments or notice any side effects, please record them in the Comments column.  
3. Please bring this form to your physician when you go for your weekly appointment.  
4. Total dose of AZD6244: ___mg ____ times per day. Total number of pills at each dose: ___.  
| 5. Total dose of capecitabine:_____mg two times per day. ____ 150 mg pills and ____500 mg pills  at each dose. AZD6244 Capecitabine Capecitabine Comments 150 mg 500 mg   |                           |                       |                     |                       |                     |                       |                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|-----------------------|---------------------|-----------------------|---------------------|-----------------------|--------------------|
| Date                                                                                                                                                                      | Day                       | # pills,  when  taken | # of  pills  missed | # pills,  when  taken | # of  pills  missed | # pills,  when  taken | # of  pills missed |
| 1 2 3 4 5 6 7 8 9 10 11 12 13                                                                                                                                             | Capecitabine is not taken |                       |                     |                       |                     |                       |                    |
| 14                                                                                                                                                                        | on these days             |                       |                     |                       |                     |                       |                    |
| 15 16 17 18 19 20                                                                                                                                                         | Capecitabine is not taken |                       |                     |                       |                     |                       |                    |
| 21                                                                                                                                                                        | on these days             |                       |                     |                       |                     |                       |                    |
| Capecitabine is not taken  on these days                                                                                                                                  |                           |                       |                     |                       |                     |                       |                    |
| Patient's signature________________________________________ Date_______________                                                                                           |                           |                       |                     |                       |                     |                       |                    |  
Patient name_____________________________ Page 2 of 2  
1. Complete this form for both AZD6244 and Capecitabine. 2. You must take AZD6244 on an empty stomach with water only, either 1 hour before or two hour after meals. Capecitabine should be taken two hours before radiation and with food.  
3. Record the date, the number of pills you took, and when you took them. 4. If you have any comments or notice any side effects, please record them in the Comments column.  
3. Please bring this form to your physician when you go for your weekly appointment.  
4. Total dose of AZD6244: ___mg ____ times per day. Number of pills at each dose: ___.  
| 5. Total dose of capecitabine:_____mg two times per day. ____ 150 mg pills and ____500  mg pills at each dose. AZD6244 Capecitabine 150  Capecitabine 500  Comments mg mg   |                           |                       |                     |                       |                     |                       |                     |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|-----------------------|---------------------|-----------------------|---------------------|-----------------------|---------------------|
| Date                                                                                                                                                                        | Day                       | # pills,  when  taken | # of  pills  missed | # pills,  when  taken | # of  pills  missed | # pills,  when  taken | # of  pills  missed |
| 22 23 24 25 26 27                                                                                                                                                           | Capecitabine is not taken |                       |                     |                       |                     |                       |                     |
| 28                                                                                                                                                                          | on these days             |                       |                     |                       |                     |                       |                     |
| 29 30 31 32 33 34                                                                                                                                                           | Capecitabine is not taken |                       |                     |                       |                     |                       |                     |
| 35                                                                                                                                                                          | on these days             |                       |                     |                       |                     |                       |                     |
| 36 37 38 39 40 41                                                                                                                                                           | Capecitabine is not taken |                       |                     |                       |                     |                       |                     |
| 42                                                                                                                                                                          | on these days             |                       |                     |                       |                     |                       |                     |
| 43 44 45 46 47                                                                                                                                                              |                           |                       |                     |                       |                     |                       |                     |
| Patient's signature________________________________________ Date_______________                                                                                             |                           |                       |                     |                       |                     |                       |                     |
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appendix e laboratory correlative studies

The biopsy specimen will be obtained at the time of pretreatment endoscopy. Biopsies will be collected, immediately placed in sterile saline on wet ice, and transported to the laboratory of Deborah Citrin. Specimens will centrifuged to remove supernatant and frozen at -80 C until transfer to the Laboratory of Pathology. Evaluation for mutations will be performed by the Laboratory of Pathology at the NCI which completes these assays as standard practice on tumor samples. If additional DNA or tissue remains and PTEN expression is absent by immunohistochemistry, pcr for amplification of PTEN exons followed by sequencing will occur in the laboratory of Dr. Deborah Citrin.  
Tumor ERK1/2 phosphorylation and PTEN expression - *Laboratory Correlative Study \#2*) The specimen will be collected at the time of pretreatment endoscopy and on day 8 and day 15. The specimen will be submitted in formalin for processing and imunohistochemistry. Immunohistochemistry will be performed with chromagen based detection using a polyclonal primary antibody directed against phospho-ERK1/2.(45, 46) If additional sample is available tumor PTEN expression will be evaluated with immunohistochemistry.
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peripheral mononuclear cell erk1/2 phosphorylation

Collection of Specimen: A whole blood specimen will be collected pretreatment, day 8, day 15, and at one month of follow up. Whole blood will be collected and transported immediately to the laboratory of Deborah Citrin for processing for flow cytometric analysis. The technique used for processing and analysis will be identical to that used by Astra Zeneca in prior trials of AZD6244.  
PBMC and plasma samples will also be collected on days 4-5 and days 11-12 for pharmacokinetic and pharmacodynamic analysis. Collection of specimen: 3 mL of whole blood will be sampled at the time points indicated below. Blood will be immediately transported to the laboratory of Deborah Citrin for processing and storage prior to shipment in batches to Astra Zeneca.  
For QD dosing these samples will be obtained at ): Pre-dose (within 10 minutes of dosing), 30 minutes, 1 hour, 1 hour 30 minutes, 2, 4, 8, 12 and 24 hours post-dose (24 hour sample is pre- the next day's dose).  
Day 11 or 12 (AZD6244 + capecitabine + radiotherapy): Pre-dose (within 10 minutes of dosing), 30 minutes, 1 hour, 1 hour 30 minutes, 2, 4, 8, 12 and 24 hours post-dose (24 hour sample is pre- the next day's dose). For BID dosing these samples will be obtained at Day 4 or 5 (AZD6244 alone): Pre-dose (within 10 minutes of dosing), 30 minutes, 1 hour, 1 hour 30 minutes, 2, 4, 8 and 12 hours post-dose (12 hour sample is pre- the next day's dose). Day 11 or 12 (AZD6244 + capecitabine + radiotherapy): Pre-dose (within 10 minutes of dosing), 30 minutes, 1 hour, 1 hour 30 minutes, 2, 4, 8 and 12 hours post-dose (12 hour sample is pre- the next day's dose).  
Plasma TGFα - *Laboratory Correlative Study \#4*)Collection of Specimen: Specimen will be collected pretreatment, day 8, day 15, and at one month of follow up. Plasma will be immediately transported on ice to the laboratory of Deborah Citrin. Plasma will be processed within 15 minutes of collection. Aliquots will be stored at -80 C until use. TGF-α levels will be assessed with the commercially available Elisa kit from R&D Systems as per manufacturer's instruction
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appendix f acute rtog

| [ 0  ]                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | [ 1 ]                                                                                                                                                                    | [ 2 ]                                                                                                    | [ 3 ]                                                                                                                                                                                                                                                                                                                 | [ 4 ]                                  |                             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------|-----------------------------|
| SKIN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | No change                                                                                                                                                                | Follicular, faint or dull erythema/                                                                      | Tender or bright erythema, patchy                                                                                                                                                                                                                                                                                     |                                        |                             |
| over                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | epilation/dry desquamation/                                                                                                                                              | moist desquamation/ moderate                                                                             | Confluent, moist desquamatiom other than skin folds,  pitting edema                                                                                                                                                                                                                                                   | Ulceration, hemorrhage, necrosis       |                             |
| baseline                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | decreased sweating                                                                                                                                                       | edema                                                                                                    |                                                                                                                                                                                                                                                                                                                       |                                        |                             |
| Anorexia with <=5% weight loss  from pretreatment baseline/ nausea                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                          |                                                                                                          |                                                                                                                                                                                                                                                                                                                       |                                        |                             |
| UPPER G.I.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | No change                                                                                                                                                                | not requiring antiemetics/ abdominal  discomfort not requiring  parasympatholytic drugs or  analgesics   | Anorexia with >15% weight loss from pretreatment  baseline or requiring N-G tube or parenteral support.  Nausea &/or vomiting requiring tube or parenteral  support/abdominal pain, severe despite  medication/hematemesis or melena/ abdominal distention  (flat plate radiograph demonstrates distended bowel loops |                                        |                             |
| Anorexia with <=15% weight loss  from pretreatment baseline/nausea  &/ or vomiting requiring  antiemetics/ abdominal pain  requiring analgesics                                                                                                                                                                                                                                                                                                                                                                                                                                   | Ileus, subacute or acute obstruction,  performation, GI bleeding requiring  transfusion/abdominal pain requiring  tube decompression or bowel diversion                  |                                                                                                          |                                                                                                                                                                                                                                                                                                                       |                                        |                             |
| Diarrhea requiring  parasympatholytic drugs (e.g.,  Lomotil)/ mucous discharge not  necessitating sanitary pads/ rectal  or abdominal pain requiring  analgesics                                                                                                                                                                                                                                                                                                                                                                                                                  | Acute or subacute obstruction, fistula  or perforation; GI bleeding requiring  transfusion; abdominal pain or  tenesmus requiring tube decompression  or bowel diversion |                                                                                                          |                                                                                                                                                                                                                                                                                                                       |                                        |                             |
| Increased frequency or change in                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                          |                                                                                                          |                                                                                                                                                                                                                                                                                                                       |                                        |                             |
| LOWER G.I.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | quality of bowel habits not requiring                                                                                                                                    |                                                                                                          |                                                                                                                                                                                                                                                                                                                       |                                        |                             |
| INCLUDING  PELVIS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | No change                                                                                                                                                                | medication/ rectal discomfort not  requiring analgesics                                                  | Diarrhea requiring parenteral support/ severe mucous or  blood discharge necessitating sanitary pags/abdominal  distention (flat plate radiograph demonstrates distended  bowel loops)                                                                                                                                |                                        |                             |
| Frequency of urination or nocturia  which is less frequent than every  hour. Dysuria, urgency, bladder  spasm requiring local anesthetic  (e.g., Pyridium)                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                          |                                                                                                          |                                                                                                                                                                                                                                                                                                                       |                                        |                             |
| GENITOURINARY                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | No change                                                                                                                                                                | Frequency of urination or nocturia  twice pretreatment habit/ dysuria,  urgency not requiring medication | Frequency with urgency and nocturia hourly or more                                                                                                                                                                                                                                                                    | Hematuria requiring transfusion/ acute |                             |
| frequently/ dysuria, pelvis pain or bladder spasm requiring  regular, frequent narcotic/gross hematuria with/ without                                                                                                                                                                                                                                                                                                                                                                                                                                                             | bladder obstruction not secondary to                                                                                                                                     |                                                                                                          |                                                                                                                                                                                                                                                                                                                       |                                        |                             |
| clot passage                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | clot passage, ulceration or necrosis                                                                                                                                     |                                                                                                          |                                                                                                                                                                                                                                                                                                                       |                                        |                             |
| HEMATOLOGIC  WBC (X 1000)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | >=4.0                                                                                                                                                                    | 3.0 - <4.0                                                                                               | 2.0 - <3.0                                                                                                                                                                                                                                                                                                            | 1.0 - <2.0                             | <1.0                        |
| PLATELETS (X  1000)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | >=100                                                                                                                                                                    | 75 - <100                                                                                                | 50 - <75                                                                                                                                                                                                                                                                                                              | 25 - <50                               | <25 or spontaneous bleeding |
| NEUTROPHILS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | >=1.9                                                                                                                                                                    | 1.5 - <1.9                                                                                               | 1.0 - <1.5                                                                                                                                                                                                                                                                                                            | 0.5 - <1.0                             | <0.5 or sepsis              |
| HEMOGLOBIN (GM  %)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | >11                                                                                                                                                                      | 11-9.5                                                                                                   | <9.5 - 7.5                                                                                                                                                                                                                                                                                                            | <7.5 - 5.0                             | -------                     |
| HEMATOCRIT (%)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | >=32                                                                                                                                                                     | 28 - <32                                                                                                 | <28                                                                                                                                                                                                                                                                                                                   | Packed cell transfusion required       | -------                     |
| GUIDELINES: The acute morbidity criteria are used to score/grade toxicity from radiation therapy. The criteria are relevant from day 1, the commencement of therapy, through day 90. Thereafter, the EORTC/RTOG  Criteria of Late Effects are to be utilized. The evaluator must attempt to discriminate between disease- and treatment-related signs and symptoms. An accurate baseline evaluation prior to commencement of therapy is necessary. All toxicities Grade 3, 4 or 5* must be verified by the Principal Investigator. * ANY TOXICITY WHICH CAUSED DEATH IS GRADED 5. |                                                                                                                                                                          |                                                                                                          |                                                                                                                                                                                                                                                                                                                       |                                        |                             |  
| APPENDIX G: LATE RTOG TOXICITY [ 0 ] [ 1 ]                                                                                                                                                                                                                                                                                                                                                                                                                                       | [ 2 ]                                                                                                                                             | [ 3 ]                                                                        | [ 4 ]                                                     |                                           |                       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|-----------------------------------------------------------|-------------------------------------------|-----------------------|
| SKIN                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | No change                                                                                                                                         | Slight atrophy                                                               | Patch atrophy; Moderate telangiectasia;                   |                                           |                       |
| Pigmentation change                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Total hair loss                                                                                                                                   | Marked atrophy; Gross telangiectasia                                         | Ulceration                                                |                                           |                       |
| Some hair loss                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Moderate fibrosis but asymptomatic                                                                                                                | Severe induration and loss of                                                |                                                           |                                           |                       |
| SUBCUTANEOUS  TISSUE                                                                                                                                                                                                                                                                                                                                                                                                                                                             | No change                                                                                                                                         | Slight induration (fibrosis) and loss of                                     | subcutaneous tissue                                       |                                           |                       |
| subcutaneous fat                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Slight field contracture                                                                                                                          | Field contracture                                                            | Necrosis                                                  |                                           |                       |
| <10% linear reduction                                                                                                                                                                                                                                                                                                                                                                                                                                                            | >10% linear measurement                                                                                                                           |                                                                              |                                                           |                                           |                       |
| Mild diarrhea                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                   |                                                                              |                                                           |                                           |                       |
| SMALL/LARGE                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Mild cramping                                                                                                                                     |                                                                              |                                                           |                                           |                       |
| INTESTINE                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | No change                                                                                                                                         | Bowel movement 5 times daily Slight rectal discharge or bleeding             | Moderate diarrhea and colic Bowel movement >5 times daily | Obstruction or bleeding requiring surgery | Necrosis/ Perforation |
| Excessive rectal mucus or intermittent                                                                                                                                                                                                                                                                                                                                                                                                                                           | Fistula                                                                                                                                           |                                                                              |                                                           |                                           |                       |
| bleeding                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Severe frequency and dysuria Severe generalized telangiectasia (often  with petechiae) Frequent hematuria Reduction in bladder capacity (<150 cc) |                                                                              |                                                           |                                           |                       |
| BLADDER                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | No change                                                                                                                                         | Slight epithelial atrophy                                                    | Moderate frequency                                        |                                           |                       |
| Minor telangiectasia (microscopic                                                                                                                                                                                                                                                                                                                                                                                                                                                | Generalized telangiectasia                                                                                                                        |                                                                              |                                                           |                                           |                       |
| hematuria)                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Intermittent macroscopic hematuria                                                                                                                | Necrosis/ Contracted bladder  (capacity <100 cc) Severe hemorrhagic cystitis |                                                           |                                           |                       |
| BONE                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | No change                                                                                                                                         | Asymptomatic                                                                 | Moderate pain or tenderness                               | Severe pain or tenderness                 |                       |
| No growth retardation                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Growth retardation                                                                                                                                | Complete arrest of bone growth Dense bone sclerosis                          | Necrosis/ Spontaneous fracture                            |                                           |                       |
| Reduced bone density                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Irregular bone sclerosis                                                                                                                          |                                                                              |                                                           |                                           |                       |
| JOINT                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | No change                                                                                                                                         | Mild joint stiffness                                                         | Moderate stiffness                                        | Severe joint stiffness                    |                       |
| Slight limitation of movement                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Intermittent or moderate joint pain                                                                                                               | Pain with severe limitation of movement                                      | Necrosis/ Complete fixation                               |                                           |                       |
| Moderate limitation of movement                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                   |                                                                              |                                                           |                                           |                       |
| GUIDELINES: The late morbidity criteria are used to score/grade toxicity from radiation therapy. The critera are relevant beginning at day 90 after therapy. The evaluator must attempt to discriminate between disease- and treatment-related signs and symptoms. An accurate baseline evaluation prior to commencement of therapy is necessary. All toxicities Grade 3, 4 or 5* must be verified by the Principal Investigator. * ANY TOXICITY WHICH CAUSED DEATH IS GRADED 5. |                                                                                                                                                   |                                                                              |                                                           |                                           |                       |