Science

Int. J. Radiation Oncology Biol. Phys., Vol. 47, No. 1, pp.
13 47, 2000 Copyright 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$see front matter
PII S0360-3016(99)00559-3
CRITICAL REVIEW
COMMON TOXICITY CRITERIA: VERSION 2.0. AN IMPROVED REFERENCE FOR GRADING THE ACUTE EFFECTS OF CANCER TREATMENT: IMPACT ON RADIOTHERAPY ANDY TROTTI, M.D.,* ROGER BYHARDT, M.D., JOANNE STETZ, R.N., CLEMENT GWEDE, R.N., M.P.H. ,* BENJAMIN CORN, M.D., KAREN FU, M.D., GUNDERSON, M.D., BERYL MCCORMICK, M.D.,# MITCHELL MORRIS, TYVIN RICH, M.D., WILLIAM SHIPLEY, M.D.,** AND WALTER CURRAN, M.D. FOR THE RADIATION THERAPY ONCOLOGY GROUP
LEONARD
*H. Lee Moftt Cancer Center, University of South Florida, Tampa, FL; Medical College of Wisconsin, Milwaukee, WI; RTOG Headquarters, Philadelphia, PA; Thomas Jefferson University Hospital/Bodine Cancer Treatment Center, Philadelphia, PA; University of California San Franciso, San Francisco, CA; Mayo Clinic, Medical School, Rochester, MN; #Memorial Sloan-Kettering, Cornell Medical College, New York, NY; University of Texas M. D. Anderson Cancer Center, Houston, TX; University of Virginia Science Center, Charlottesville, VA; **Massachusetts General Hospital, Harvard Medical School, Boston, MA In 1997, the National Cancer Institute (NCI) led an effort to revise and expand the Common Toxicity Criteria (CTC) with the goal of integrating systemic agent, radiation, and surgical criteria into a comprehensive and standardized system. Representatives from the Radiation Therapy Oncology Group (RTOG) participated in this process in an effort to improve acute radiation related criteria and to achieve better clarity and consistency among modalities. CTC v. 2.0 replaces the previous NCI CTC and the RTOG Acute Radiation Morbidity Scoring Criteria and includes more than 260 individual adverse events with more than 100 of these applicable to acute radiation effects. One of the advantages of the revised criteria for radiation oncology is the opportunity to grade acute radiation effects not adequately captured under the previous RTOG system. A pilot study conducted by the RTOG indicated the new criteria are indeed more comprehensive and were preferred by research associates. CTC v. 2.0 represents an improvement in the evaluation and grading of acute toxicity for all modalities. 2000 Elsevier Science Inc. Toxicity, Acute effects, Side effects, Adverse events, Morbidity, Complications, Normal tissue effects, Radiation, Chemotherapy, Chemoradiation, Combined modality.
INTRODUCTION The recognition and grading of toxicity caused by cancer treatment is an important aspect of radiation oncology practice and a critical endpoint in clinical trials. Prior to 1985, the radiotherapy literature carried a variety of inconsistent descriptions and ad hoc terminology for radiation-related toxicity. A similar problem existed in the chemotherapy literature. In 1982, the National Cancer Institute (NCI) created the Common Toxicity Criteria (CTC) for chemotherapy-related effects and the Radiation Therapy Oncology Group (RTOG) developed the Acute Radiation Morbidity Scoring Criteria for radiation effects. Separate criteria were also developed for the late effects of radiation (1). These systems have now been in place for more than 15 years and have been crucial to the identication and reporting of toxicity in clinical trials. However, as new toxicities
Reprint requests to: Dr. Andy Trotti, Division of Radiation Oncology, H. Lee Moftt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612-9497. E-mail: trotti@moftt.usf.edu AcknowledgmentsThanks also to Joyce Neading, R.N., Bonnie
13
were observed, CTC users found it necessary to create new criteria or modify old criteria for specic purposes, leading to inconsistencies and confusion in grading among investigators and cooperative groups. In addition, some of the original criteria included descriptions of multiple adverse events within the same item, making it impossible to tell which specic event had occurred. It was therefore recognized that an expanded and improved set of criteria for acute effects were needed. This report will describe the revised Common Toxicity Criteria and its impact on toxicity grading in radiotherapy. METHODS In 1997, the NCI Cancer Therapy Evaluation Program (CTEP) led an effort to revise and expand the CTC and to merge systemic, radiation, and surgical criteria into one
Sauder, R.N., and Anne Wooten, R.N., who assisted in the data collection comparison study. Accepted for publication 9 December 1999.
14
I. J. Radiation Oncology
Biology
Physics
Volume 47, Number 1, 2000
comprehensive and standardized system. Representatives from the U.S. cooperative groups, many international cooperative groups, the pharmaceutical industry, and the World Health Organization (WHO) participated in the process. The RTOG appointed a panel consisting of Disease Site Chairs charged with suggesting revisions to the RTOG Acute Toxicity Criteria. Their suggestions were integrated with the recommendations and language from other groups and modality representatives. The product of that effort was titled Common Toxicity Criteria: Version 2.0 (CTC v. 2.0) and was made available on the NCI/CTEP web site in early 1998. CTC v. 2.0 now includes more than 260 individual adverse events (previously 49) organized by 24 different organ or physiologic systems (previously 13). The substantial increase in the number of items was mostly a result of splitting some complex criteria into two or more items. There has been no change in the conceptual ranking of severity, which includes ve grades: Grade 0 absent or none; grade 1mild; grade 2moderate; grade 3severe and undesirable; grade 4 life-threatening or disabling; grade 5 death. In general, modications in terminology were made only for clarication and consistency with the intent of preserving the content and severity scaling of the previous system. The term toxicity is not clearly dened by the NCI or other regulatory organizations. The generic term adverse event is preferred since some events may or may not be related to treatment. Assignment of attribution is required on NCI-sponsored investigational new drug studies using ve specic codes describing the relationship of the event to treatment as denite, probable, possible, unlikely or unrelated. The term toxicity is generally used when an adverse event is attributed to treatment in the rst three categories.
RESULTS A full reproduction of the most recent version of CTC v. 2.0 is included at the end of this report (Appendix A). CTC v. 2.0 is also available on the NCI/CTEP web site (2). It is considered a dynamic document and will be updated regularly as necessary. Readers are urged to view the web site for the most up-to-date version. A complete description of all modications in the previous RTOG or CTC criteria is beyond the scope of this report, but an overview with a few signicant changes and examples will be presented. When merging the previous RTOG Acute Radiation Morbidity Scoring Criteria with the CTC system, it was clear that much of the criteria language and scoring elements were similar. In many cases, radiation criteria were not necessarily specic to radiotherapy and therefore, generic language applicable to multiple modalities was selected. However, four radiation-specic criteria were felt to be sufciently distinctive from chemotherapy descriptors: radiation mucositis, radiation dermatitis, pharyngeal dyspha-
gia, and esophageal dysphagia (see discussion for grading of toxicity in concurrent chemoradiotherapy). Some of the previous RTOG criteria included pain as a descriptive element, which inuenced the severity grading of a local toxicity. In CTC v. 2.0, pain thought to be due to radiotherapy is graded separately from other local effects under Pain, due to radiation found in the PAIN category. In addition, it was decided to change the grading of radiation-related pain by its interference with function or activities (previously by the need for analgesics) to conform to other CTC pain criteria. In the head and neck region, the previous RTOG criteria (mucous membrane, skin, pharynx and esophagus, salivary gland, larynx) have been improved and merged into the new CTC. Radiation dermatitis is now found in the DERMATOLOGY/SKIN category. The previous pharynx and esophagus were split into two separate criteria, now found in the GASTROINTESTINAL category as Dysphagiapharyngeal, related to radiation and Dysphagia-esophageal, related to radiation. Larynx toxicity is now under PULMONARY and is called Voice changes/stridor/larynx with a footnote calling for separate grading for cough and mucositis. Ear has been split into external canal, middle and inner ear found in AUDITORY/HEARING. Salivary gland and mucous membrane (now, mucositis, due to radiation) are also found in the GASTROINTESTINAL category. The descriptors for radiation mucositis were modied for clarity. There has been substantial variation in the literature regarding the use of the terms mucositis and stomatitis. Stomatitis (oral mucositis), as dened by CTC v. 2.0, is a chemotherapy-related toxicity evident as ulcers (predominantly noted in the oral cavity) interfering with the ability to eat. Mucositis not due to radiation (i.e., from a systemic agent) is coded separately under the organ affected (e.g., Colitis, Esophagitis, Gastritis, Typhlitis, Vaginitis). Mucositis due to radiation is a radiation effect graded by the extent of mucosal ulceration/pseudomembrane noted in the treatment portal. This, of course, can be noted in the head and neck, esophagus, or other mucosal surfaces examined by direct visualization or endoscopy. Pain from radiation mucositis is graded separately under Pain, due to radiation. While the pathophysiology of acute mucosal injuries from radiation or chemotherapy are similar, the temporal patterns and anatomic distributions usually differ. Mucositis can of course be exacerbated by chemotherapy but should be scored by radiation criteria if the injury occurs within the portal. The previous RTOG central nervous system (CNS) criteria are now replaced by more than 30 specic symptomrelated criteria found in the NEUROLOGY category that focus on interference with function or activities of daily living. The previous RTOG lung criteria are replaced by specic criteria for cough, dyspnea, forced expiratory volume in 1 second (FEV1), pneumonitis, effusion, and adult respiratory distress syndrome (ARDS). Pulmonary brosis is also listed in the CTC for the effects of chemotherapy, but
Impact of Common Toxicity Criteria v. 2.0 on radiotherapy
A. TROTTI et al.
15
a footnote directs the user to grade radiation-related pulmonary brosis by the RTOG Late Radiation Morbidity Scoring Schema, which is found in Appendix IV of the CTC 2.0. The previous RTOG upper GI and lower GI criteria are replaced by more than 20 GASTROINTESTINAL criteria that can be used for radiation effects. The previous RTOG genitourinary criteria are replaced by at least six criteria that apply to radiation effects in the RENAL/GENITOURINARY category. Gynecologic issues and those related to male and female sexual function are found in the SEXUAL/ REPRODUCTIVE FUNCTION category. RTOG pilot study of revised criteria A small pilot study was conducted by RTOG investigators and clinical research associates (CRAs) to determine if substantial changes in assignment of numerical grade can be expected with the new versus the old criteria (unpublished data). Four CRAs were trained by a representative from the NCI to use the revised system. The medical records and RTOG report forms of 68 patients at three institutions enrolled in 15 different RTOG clinical trials involving lung, brain, abdominal, pelvic, or head and neck cancer were reviewed. Acute toxicities of radiation therapy or chemoradiation previously reported using the RTOG acute toxicity scoring criteria alone (or in conjunction with the old CTC) were rescored using the revised scoring system (CTC v. 2.0). The proportion of concordance (or discordance) between the two sets of criteria was examined. The two scoring systems were also evaluated for general preference by RTOG CRAs. The ndings were consistent with expectations and showed that the revised system generally increased the number of toxicities reported in each organ category. For example, the mean number of items reported per patient for dermatology/skin was 0.88 for the old system compared to 1.07 for the new system. Similarly, the gastrointestinal toxicities increased from 1.96 for the old criteria to 2.63 under the new system, primarily as a result of the splitting of previous complex criteria in the old systems into multiple criteria in the new system. In addition, newly created criteria allowed the grading of previously unreported toxicity. The new criteria increased the magnitude of toxicity one grade level in 11%, and decreased it in 5% of the charts reviewed. Overall, there were no signicant differences in the distribution of the magnitude of toxicity grades between the two scoring systems; that is, no marked trend toward increasing or decreasing the grade of a toxicity was noted. Since the primary goal of the revision was to expand and improve clarity without changing the magnitude of the grades. The lack of statistical differences in our analyses is consistent with the effort to preserve the overall scaling of the grading system. In addition, RTOG CRAs preferred using the new system and found it to be more comprehensive than the previous criteria. For example, CRAs stated that the new system allowed better scoring of additional toxicities not included in the previous system. Improvements in terminology and
clarity of language were also felt to facilitate the grading of some toxicities. DISCUSSION CTC v. 2.0 is a more comprehensive and improved reference for the grading of acute toxicity for all modalities. It has been in use for all NCI-sponsored trials since March 1998. Additional changes and improvements will be made on a regular basis. Readers are urged to view the NCI/CTEP web site for the most up-to-date version (3). Discussions are underway between the NCI and the newly created American College of Surgeons Oncology Group to consider additional revisions and expansion of surgically related criteria. CTC v. 2.0 replaces the previous RTOG Acute Radiation Morbidity Criteria (containing 13 individual criteria) and includes more than 100 criteria applicable to the acute effects of radiotherapy. One of the advantages of the revised CTC for radiation oncology is the opportunity to score acute radiation toxicities not included or well-dened in the previous RTOG system. These include change in weight, anorexia, nausea, gastritis/ulcers, changes in hepatic function, myalgia, changes in smell and taste, fatigue, pruritus, cellulitis, and edema. In addition, the use of separate criteria describing specic clinical events (e.g., CTC nausea, vomiting, diarrhea, weight loss, abdominal pain) which were encompassed in a combined organ or regional description (e.g., RTOG upper G.I.) in the previous system, provides more detailed information for the interpretation and reporting of toxicity. For a patient receiving concurrent chemoradiotherapy, toxicity should be graded using the criteria that best describe the event. In most cases, epithelial toxicity in the radiation eld will be best described using the radiationspecic criteria for mucositis, dermatitis, and dysphagia. Pain in the radiation eld felt to be related to these local toxicities should also be scored under Pain, due to radiation. The grading should not be modied to account for any possible increased effect or exacerbation by chemotherapy. The interpretation of toxicity data and assignment of causal effect is considered the responsibility of the principal investigator of the trial. A pilot study of the new system reveals that it allows more specic scoring of individual toxicities, yet preserves the severity scaling of the previous system. RTOG CRAs preferred using the new system and found it to be more comprehensive and easier to interpret than the previous criteria. The detailed and comprehensive nature of the revised CTC has also yielded a rather lengthy document (33 pages) which may be impractical to attach physically to a protocol. Investigators may want to create a protocol-specic checklist of expected toxicities and refer to the master document for additional criteria as needed. The NCI has developed a number of on-line tools to facilitate learning and using the revised CTC (2). The CTC Manual provides background information, instructions, and examples for investigators (5). An interactive tool to facil-
16
Biology
Physics
itate navigation through the revised CTC provides assistance in identication and grading of adverse events. This tool is also being adapted for use in palm-sized personal computers. A conversion tool for the mapping of CTC (version 1.0) to CTC v. 2.0 is available on the NCI website, but no such tool is available for the previous RTOG criteria. The accuracy or validity of the grading criteria is not completely certain. Both versions of the CTC were developed through focus group discussion and consensus of oncology experts. There has not been a systematic evaluation of the CTC for validity or reliability between different observers. Some criteria are quantitative and easily applied (lab values), whereas others are more qualitative or subjec-
tive (neurologic-related changes in function/activities, edema, dry mouth). Although clarications have been made in the revised system, the application of some criteria may still vary among observers (3). It has also been recognized that the RTOG Late Radiation Morbidity Scoring Criteria are in need of revision. In 1995, the LENT/SOMA system was published as a more comprehensive and detailed system (4). The RTOG has conducted a formal validation study of the head and neck module of the LENT/SOMA system and results are pending at the time of this report. The goal is to determine which elements of the LENT/SOMA system are critical to full and accurate grading and to complete the development of a more comprehensive system for late effects.
REFERENCES
1. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:13411346. 2. Arbuck SG, Ivy SP, Setser A, et al. The Revised Common Toxicity Criteria: Version 2.0. CTEP Website. http://ctep.info. nih.gov. 3. Brundage MD, Pater JL, Zee B. Assessing the reliability of two toxicity scales: Implications for interpreting toxicity data. J Natl Cancer Inst 1993;85:1138 1148. 4. Rubin P. Late Effects of Normal Tissues (LENT) Consensus Conference. Radiat Oncol Biol Phys 1995;31:10351367. 5. Arbuck SG, McClure J, Ivy SP, Setser A. The Common Toxicity Criteria Manual. CTEP Website, http://ctep.info.nih.gov.
APPENDIX A COMMON TOXICITY CRITERIA (CTC)

Grade Adverse Event 0 1 2 3 4
ALLERGY/IMMUNOLOGY Allergic none reaction/hypersensitivity (including drug fever) anaphylaxis urticaria, drug fever symptomatic 38C ( 100.4F), bronchospasm, and/or requiring parenteral asymptomatic medication(s), with bronchospasm or without urticaria; allergy-related edema/angioedema Note: Isolated urticaria, in the absence of other manifestations of an allergic or hypersensitivity reaction, is graded in the DERMATOLOGY/SKIN category. transient rash, drug fever 38C ( 100.4F) Allergic rhinitis (including sneezing, nasal stufness, postnasal drip) Autoimmune reaction none mild, not requiring treatment moderate, requiring treatment
reversible autoimmune autoimmune reaction evidence of serologic or other causing major reaction involving autoimmune evidence of grade 4 organ function of a major reaction involving a autoimmune dysfunction; organ or other nonessential organ reaction but patient progressive and adverse event (e.g., or function (e.g., is asymptomatic irreversible transient colitis or hypothyroidism), (e.g., vitiligo), all reaction; long-term anemia), requiring requiring treatment organ function is administration of short-term other than normal and no high-dose immunosuppressive immunosuppressive treatment is immunosuppressive treatment drugs required therapy required Also consider Hypothyroidism, Colitis, Hemoglobin, Hemolysis. none Serum sickness none present
Urticaria is graded in the DERMATOLOGY/SKIN category if it occurs as an isolated symptom. If it occurs with other manifestations of allergic or hypersensitivity reaction, grade as Allergic reaction/hypersensitivity above. Vasculitis none mild, not requiring treatment symptomatic, requiring medication moderate requiring steroids ischemic changes or requiring amputation life-threatening or disabling
Allergy/ ImmunologyOther (Specify, )
none
mild
severe
AUDITORY/HEARING Conductive hearing loss is graded as Middle ear/hearing in the AUDITORY/HEARING category. Earache is graded in the PAIN category. external otitis with external otitis with external otitis with necrosis of the canal erythema or dry moist desquamation discharge, soft tissue or bone desquamation mastoiditis Note: Changes associated with radiation to external ear (pinnae) are graded under Radiation dermatitis in the DERMATOLOGY/SKIN category. External auditory canal normal
17
18
Biology
Physics
Grade Adverse Event Inner ear/hearing normal 0 1 hearing loss on audiometry only 2 tinnitus or hearing loss, not requiring hearing aid or treatment 3 tinnitus or hearing loss, correctable with hearing aid or treatment otitis with discharge, mastoiditis or conductive hearing loss 4 severe unilateral or bilateral hearing loss (deafness), not correctable necrosis of the canal soft tissue or bone
Middle ear/hearing
normal
serous otitis without serous otitis or subjective decrease infection requiring in hearing medical intervention; subjective decrease in hearing; rupture of tympanic membrane with discharge mild moderate
Auditory/ HearingOther (Specify, )
normal
severe
life-threatening or disabling
BLOOD/BONE MARROW Bone marrow cellularity normal for age mildly hypocellular moderately or 25% reduction hypocellular or from normal 25 50% cellularity for age reduction from normal cellularity for age or 2 but 4 weeks to recovery of normal bone marrow cellularity severely hypocellular or 50 75% reduction in cellularity for age or 46 weeks to recovery of normal bone marrow cellularity aplasia or 6 weeks to recovery of normal bone marrow cellularity
Normal ranges: children ( 18 years) 90% cellularity average younger adults (1959) older adults ( 60 years) 6070% cellularity average 50% cellularity average
Note: Grade Bone marrow cellularity only for changes related to treatment not disease. CD4 count Haptoglobin Hemoglobin (Hgb) WNL normal WNL LLN500/mm3 decreased LLN10.0 g/dL LLN100 g/L LLN6.2 mmol/L 10 25% decrease from pretreatment 200 500/mm3 8.0 10.0 g/dL 80 100 g/L 4.9 6.2 mmol/L 25 50% decrease from pretreatment 50 200/mm3 absent 6.5 8.0 g/dL 65 80 g/L 4.0 4.9 mmol/L 50 75% decrease from pretreatment 50/mm3 6.5 g/dL 65 g/L 4.0 mmol/L 75% decrease from pretreatment
For leukemia studies WNL or bone marrow inltrative/ myelophthisic processes, if specied in the protocol.
A. TROTTI et al.
19
Grade Adverse Event Hemolysis (e.g., immune hemolytic anemia, drugrelated hemolysis, other) none 0 1 only laboratory evidence of hemolysis (e.g., direct antiglobulin test [DAT, Coombs] schistocytes) 2 evidence of red cell destruction and 2 gm decrease in hemoglobin, no transfusion 3 requiring transfusion and/or medical intervention (e.g., steroids) 4 catastrophic consequences of hemolysis (e.g., renal failure, hypotension, bronchospasm, emergency splenectomy) 1.0 109/L 1000/mm3 0.5 109/L 500/mm3 25% LLN
Also consider Haptoglobin, Hemoglobin. Leukocytes (total WBC) For BMT studies, if specied in the protocol. For pediatric BMT studies (using age, race and sex normal values), if specied in the protocol. Lymphopenia For pediatric BMT studies (using age, race and sex normal values), if specied in the protocol. Neutrophils/ granulocytes (ANC/AGC) For BMT studies, if specied in the protocol. For leukemia studies or bone marrow inltrative/ myelophthisic process, if specied in the protocol. Platelets WNL WNL WNL LLN3.0 109/L LLN3000/mm3 2.0 3.0 109/L 2000 3000/mm3 75 100% LLN 2.0 3.0 109/L 2000 3000/mm3 1.0 2.0 109/L 1000 2000/mm3 50 75% LLN 1.0 2.0 109/L 1000 2000/mm3 0.5 1.0 109/L 500 1000/mm3 2550% LLN
WNL
LLN1.0 109/L LLN1000/mm3 75 100% LLN
0.5 1.0 109/L 500 1000/mm3 50 75% LLN
0.5 109/L 500/mm3 25 50% LLN
25% LLN
1.5 2.0 109/L 1500 2000/mm3 1.0 1.5 109/L 1000 1500/mm3 10 25% decrease from baseline
0.5 109/L 500/mm3 0.1 109/L 100/mm3 75% decrease from baseline
WNL
WNL
WNL
LLN75.0 109/L LLN75,000/mm3
50.0 75.0 109/L 50,000 75,000/ mm3 20.0 50.0 109/L 20,000 50,000/ mm3
10.0 50.0 109/L 10,000 50,000/ mm3 10.0 20.0 109/L 10,000 20,000/ mm3
10.0 109/L 10,000/mm3
For BMT studies, if specied in the protocol.
WNL
50.0 75.0 109/L 50,000 75,000/ mm3
10.0 109/L 10,000/mm3
20
Biology
Physics
Grade Adverse Event WNL For leukemia studies or bone marrow inltrative/myelophthisic process, if specied in the protocol. Transfusion: Platelets none 0 1 10 25% decrease from baseline 2 25 50% decrease from baseline 3 50 75% decrease from baseline 4 75% decrease from baseline
yes
platelet transfusions and other measures required to improve platelet increment; platelet transfusion refractoriness associated with life-threatening bleeding. (e.g., HLA or cross matched platelet transfusions) platelet transfusions and other measures required to improve platelet increment; platelet transfusion refractoriness associated with life-threatening bleeding. (e.g., HLA or cross matched platelet transfusions)
none
1 platelet transfusion in 24 hours
2 platelet transfusions in 24 hours
3 platelet transfusions in 24 hours
Also consider Platelets. Transfusion: pRBCs For BMT studies, if specied in the protocol. none none 2 u pRBC in 24 hours elective or planned 3 u pRBC in 24 hours elective or planned yes 4 u pRBC in 24 hours hemorrhage or hemolysis associated with life-threatening anemia; medical intervention required to improve hemoglobin hemorrhage or hemolysis associated with life-threatening anemia; medical intervention required to improve hemoglobin
For pediatric BMT studies, if specied in the protocol.
none
15 mL/kg in 24 hours elective or planned
15 30 mL/kg in 24 hours elective or planned
30 mL/kg in 24 hours
Also consider Hemoglobin. Blood/Bone MarrowOther (Specify, ) none mild moderate severe life-threatening or disabling
A. TROTTI et al.
21
CARDIOVASCULAR (ARRHYTHMIA) Conduction abnormality/ Atrioventricular heart block none asymptomatic, not requiring treatment (e.g., Mobitz type I second-degree AV block, Wenckebach) symptomatic, but not requiring treatment symptomatic and requiring treatment (e.g., Mobitz type II second-degree AV block, thirddegree AV block) symptomatic and requiring treatment life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock)
Nodal/junctional arrhythmia/ dysrhythmia
none
asymptomatic, not requiring treatment
symptomatic, but not requiring treatment
life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock)
Palpitations none present Note: Grade palpitations only in the absence of a documented arrhythmia. Prolonged QTc interval (QTc 0.48 seconds) none asymptomatic, not requiring treatment symptomatic, but not requiring treatment
symptomatic and requiring treatment
life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock) life-threatening (e.g., arrhythmia associated with CHF, hypotension syncope, shock)
Sinus bradycardia
none
symptomatic and requiring treatment
Sinus tachycardia
none
symptomatic and requiring treatment of underlying cause symptomatic and requiring treatment
Supraventricular arrhythmias (SVT/atrial brillation/ utter)
none
Syncope (fainting) is graded in the NEUROLOGY category. Vasovagal episode Ventricular arrhythmia (PVCs/bigeminy/ trigeminy/ ventricular tachycardia) Cardiovascular/ Arrhythmia Other (Specify, ) none present without loss of consciousness symptomatic, but not requiring treatment present with loss of consciousness symptomatic and requiring treatment
none
none
symptomatic, and requiring treatment of underlying cause
22
Biology
Physics
CARDIOVASCULAR (GENERAL) Acute vascular leak syndrome absent symptomatic, but not requiring uid support asymptomatic, STand T-wave changes suggesting ischemia asymptomatic but resting ejection fraction below LLN for laboratory or decline of resting ejection fraction 20% of baseline value; 24% shortening fraction respiratory compromise or requiring uids angina without evidence of infarction CHF responsive to treatment life-threatening; requiring pressor support and/or ventilatory support acute myocardial infarction
Cardiac-ischemia/ infarction
none
nonspecic T-wave attening or changes asymptomatic decline of resting ejection fraction of 10% but 20% of baseline value; shortening fraction 24% but 30%
Cardiac left ventricular function
normal
severe or refractory CHF or requiring intubation
CNS cerebrovascular ischemia is graded in the NEUROLOGY category. Cardiac troponin I (cTnI) normal levels consistent with unstable angina as dened by the manufacturer 0.1 0.2 ng/mL symptomatic edema limiting function and unresponsive to therapy or requiring drug discontinuation requiring therapy or more intensive therapy than previously levels consistent with myocardial infarction as dened by the manufacturer 0.2 ng/mL anasarca (severe generalized edema)
Cardiac troponin T (cTnT) Edema
normal none
0.03 0.05 ng/ mL asymptomatic, not requiring therapy
0.05 0.1 ng/mL symptomatic, requiring therapy
Hypertension
none
asymptomatic, transient increase by 20 mmHg (diastolic) or to 150/100* if previously WNL; not requiring treatment
recurrent or persistent or symptomatic increase by 20 mmHg (diastolic) or to 150/100* if previously WNL; not requiring treatment
hypertensive crisis
*Note: For pediatric patients, use age and sex appropriate normal values Hypotension none changes, but not requiring therapy (including transient orthostatic hypotension)
95th percentile ULN. requiring therapy and sustained medical attention, but resolves without persisting physiologic consequences shock (associated with acidemia and impairing vital organ function due to tissue hypoperfusion)
requiring brief uid replacement or other therapy but not hospitalization; no physiologic consequences
Also consider Syncope (fainting). Notes: Angina or MI is graded as Cardiac-ischemia/infarction in the CARDIOVASCULAR (GENERAL) category. For pediatric patients, systolic BP 65 mmHg or less in infants up to 1 year old and 70 mmHg or less in children older than 1 year of age, use two successive or three measurements in 24 hours.
A. TROTTI et al.
23
Grade Adverse Event Myocarditis Operative injury of vein/artery none none 0 primary suture repair for injury, but not requiring transfusion asymptomatic effusion, not requiring treatment 1 primary suture repair for injury, requiring transfusion pericarditis (rub, ECG changes, and/or chest pain) brief episode of ischemia managed nonsurgically and without permanent decit 2 3 CHF responsive to treatment vascular occlusion requiring surgery or bypass for injury with physiologic consequences 4 severe or refractory CHF myocardial infarction; resection of organ (e.g., bowel, limb) tamponade (drainage or pericardial window required) life-threatening or with permanent functional decit (e.g., amputation)
Pericardial none effusion/pericarditis
Peripheral arterial ischemia
none
requiring surgical intervention
Phlebitis none present (supercial) Notes: Injection site reaction is graded in the DERMATOLOGY/SKIN category. Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category. Syncope (fainting) is graded in the NEUROLOGY category. Thrombosis/ embolism none deep vein thrombosis, not requiring anticoagulant
deep vein thrombosis, requiring anticoagulant therapy requiring surgical intervention
embolic event including pulmonary embolism
Vein/artery operative injury is graded as Operative injury of vein/artery in the CARDIOVASCULAR (GENERAL) category. Visceral arterial ischemia (nonmyocardial) none brief episode of ischemia managed nonsurgically and without permanent decit moderate life-threatening or with permanent functional decit (e.g., resection of ileum) life-threatening or disabling
Cardiovascular/ GeneralOther (Specify, )
none
mild
severe
COAGULATION Note: See the HEMORRHAGE category for grading the severity of bleeding events. DIC absent (disseminated intravascular coagulation) Also consider Platelets. Note: Must have increased brin split products or D-dimer in order to grade as DIC. Fibrinogen For leukemia studies or bone marrow inltrative/ myelophthisic process, if specied in the protocol. WNL WNL 0.75 1.0 LLN 20% decrease from pretreatment value or LLN 0.5 0.75 LLN laboratory ndings present with no bleeding laboratory ndings and bleeding
0.25 0.5 LLN 40 70% decrease from pretreatment value or LLN
0.25 50 mg
LLN
20 40% decrease from pretreatment value or LLN
24
Biology
Physics
Grade Adverse Event Partial thromboplastin time (PTT) Prothrombin time (PT) WNL 0 1 ULN 1.5 ULN 1.5 2 2 ULN 2 3 ULN 4
Phlebitis is graded in the CARDIOVASCULAR (GENERAL) category. WNL ULN 1.5 ULN 1.5 2 ULN 2 ULN
Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category. Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura/TTP or hemolytic uremic syndrome/HUS) absent laboratory ndings present without clinical consequences laboratory ndings and clinical consequences (e.g., CNS hemorrhage/ bleeding or thrombosis/ embolism or renal failure) requiring therapeutic intervention evidence of RBC destruction with renal failure requiring dialysis and/or encephalopathy
evidence of RBC destruction (schistocytosis) without clinical consequences
evidence of RBC destruction with elevated creatinine ( 3 ULN)
evidence of RBC destruction with creatinine ( 3 ULN) not requiring dialysis
Also consider Hemoglobin, Platelets, Creatinine. Note: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). CoagulationOther (Specify, ) none mild moderate severe life-threatening or disabling
CONSTITUTIONAL SYMPTOMS Fatigue (lethargy, malaise, asthenia) none increased fatigue over baseline, but not altering normal activities moderate (e.g., decrease in performance status by 1 ECOG level or 20% Karnofsky or Lansky) or causing difculty performing some activities severe (e.g., decrease in performance status by 2 ECOG levels or 40% Karnofsky or Lansky) or loss of ability to perform some activities bedridden or disabling
Note: See Appendix III for performance status scales. Fever (in the absence none 38.039.0C of neutropenia, (100.4102.2F) where neutropenia is dened as AGC 1.0 109/L) Also consider Allergic reaction/hypersensitivity. 39.140.0C (102.3104.0F) 40.0C ( 104.0F) for 24 hr 40.0C ( 104.0F) for 24 hr
Note: The temperature measurements listed above are oral or tympanic. Hot ashes/ushes are graded in the ENDOCRINE category. Rigors, chills none mild, requiring symptomatic treatment (e.g., blanket) or nonnarcotic medication severe and/or prolonged, requiring narcotic medication not responsive to narcotic medication
A. TROTTI et al.
25
Grade Adverse Event Sweating (diaphoresis) 0 normal 1 mild and occasional 2 frequent or drenching 3 4
Weight gain 5% 5 10% 10 20% Also consider Ascites, Edema, Pleural effusion (nonmalignant). 2% 2 5% 5 10% Weight gain associated with venoocclusive disease (VOD) for BMT studies, if specied in the protocol. Also consider Ascites, Edema, Pleural effusion (nonmalignant). Weight loss 5% 5 10% 10 20%
20% 10% or as ascites
10% or uid retention resulting in pulmonary failure
20%
Also consider Vomiting, Dehydration, Diarrhea. Constitutional Symptoms Other (Specify, ) DERMATOLOGY/SKIN Alopecia normal mild hair loss pronounced hair loss Bruising (in none localized or in generalized absence of dependent area grade 3 or 4 thrombocytopenia) Note: Bruising resulting from grade 3 or 4 thrombocytopenia is graded as Petechiae/purpura and Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia in the HEMORRHAGE category, not in the DERMATOLOGY/SKIN category. Dry skin Erythema multiforme (e.g., StevensJohnson syndrome, toxic epidermal necrolysis) Flushing Handfoot skin reaction normal absent controlled with emollients not controlled with emollients scattered, but not generalized severe or requiring IV uids (e.g., generalized rash or painful stomatitis) life-threatening (e.g., exfoliative or ulcerating dermatitis or requiring enteral or parenteral nutritional support) none mild moderate severe life-threatening or disabling
absent none
present skin changes or dermatitis without pain (e.g., erythema, peeling) pain or itching or erythema
skin changes with pain, not interfering with function
skin changes with pain, interfering with function
Injection site reaction
none
pain or swelling, with inammation or phlebitis
ulceration or necrosis that is severe or prolonged, or requiring surgery
Nail changes
normal
discoloration or ridging (koilonychia) or pitting
partial or complete loss of nail(s) or pain in nailbeds
Petechiae is graded in the HEMORRHAGE category.
26
Biology
Physics
Grade 4 Adverse Event Photosensitivity none 0 1 painless erythema 2 painful erythema 3 erythema with desquamation
Pigmentation changes (e.g., vitiligo) Pruritus
none
localized pigmentation changes mild or localized, relieved spontaneously or by local measures
generalized pigmentation changes intense or widespread, relieved spontaneously or by systemic measures
none
intense or widespread and poorly controlled despite treatment
Purpura is graded in the HEMORRHAGE category. Radiation dermatitis none faint erythema or dry desquamation moderate to brisk erythema or a patchy moist desquamation, mostly conned to skin folds and creases; moderate edema conuent moist desquamation 1.5 cm diameter and not conned to skin folds; pitting edema skin necrosis or ulceration of full thickness dermis; may include bleeding not induced by minor trauma or abrasion
Note: Pain associated with radiation dermatitis is graded separately in the PAIN category as Pain due to radiation. Radiation recall reaction (reaction following chemotherapy in the absence of additional radiation therapy that occurs in a previous radiation port) Rash/desquamation none faint erythema or dry desquamation moderate to brisk erythema or a patchy moist desquamation, mostly conned to skin folds and creases; moderate edema conuent moist desquamation 1.5 cm diameter and not conned to skin folds; pitting edema skin necrosis or ulceration of full thickness dermis; may include bleeding not induced by minor trauma or abrasion
none
macular or papular eruption or erythema without associated symptoms
macular or papular eruption or erythema with pruritus or other associated symptoms covering 50% of body surface or localized desquamation or other lesions covering 50% of body surface area
symptomatic generalized erythroderma or macular, papular or vesicular eruption or desquamation covering 50% of body surface area
generalized exfoliative dermatitis or ulcerative dermatitis
Also consider Allergic reaction/hypersensitivity. Note: Stevens-Johnson syndrome is graded separately as Erythema multiforme in the DERMATOLOGY/SKIN category. Rash/dermatitis associated with high-dose chemotherapy or BMT studies. none faint erythema or dry desquamation moderate to brisk erythema or a patchy moist desquamation, mostly conned to skin folds and creases; moderate edema conuent moist desquamation 1.5 cm diameter and not conned to skin folds; pitting edema skin necrosis or ulceration of full thickness dermis; may include spontaneous bleeding not induced by minor trauma or abrasion
A. TROTTI et al.
27
Grade Adverse Event Rash/desquamation none associated with graft versus host disease (GVHD) for BMT studies, if specied in the protocol. 0 1 macular or papular eruption or erythema covering 25% of body surface area without associated symptoms 2 macular or papular eruption or erythema with pruritus or other associated symptoms covering 25 50% of body surface or localized desquamation or other lesions covering 25 50% of body surface area 3 symptomatic generalized erythroderma or symptomatic macular, papular or vesicular eruption, with bullous formation, or desquamation covering 50% of body surface area 4 generalized exfoliative dermatitis or ulcerative dermatitis or bullous formation
Also consider Allergic reaction/hypersensitivity. Note: Stevens-Johnson syndrome is graded separately as Erythema multiforme in the DERMATOLOGY/SKIN category. Urticaria (hives, welts, wheals) none requiring no medication requiring PO or topical treatment or IV medication or steroids for 24 hours supercial infection incisional hernia requiring IV medication or steroids for 24 hours infection requiring IV antibiotics fascial disruption without evisceration severe
Wound infectious Wound noninfectious Dermatology/ Skin Other (Specify, )
none none
cellulitis incisional separation
necrotizing fasciitis fascial disruption with evisceration life-threatening or disabling
none
mild
moderate
ENDOCRINE Cushingoid appearance (e.g., moon face, buffalo hump, centripetal obesity, cutaneous striae) absent present
Also consider Hyperglycemia, Hypokalemia. Feminization of male Gynecomastia absent none mild pronounced or painful present pronounced or painful and requiring surgery patient hospitalized for manifestations of hypothyroidism present
Hot ashes/ushes Hypothyroidism
none absent
mild or no more than 1 per day asymptomatic, TSH elevated, no therapy given
moderate and greater than 1 per day symptomatic or thyroid replacement treatment given
myxedema coma
Masculinization of female
absent
28
Biology
Physics
Grade Adverse Event SIADH (syndrome of inappropriate antidiuretic hormone) EndocrineOther (Specify, ) 0 absent 1 2 present 3 4
none
mild
moderate
severe
GASTROINTESTINAL Amylase is graded in the METABOLIC/LABORATORY category. Anorexia none loss of appetite oral intake signicantly decreased symptomatic, requiring diuretics requiring IV uids requiring feeding tube or parenteral nutrition life-threatening physiologic consequences
Ascites (nonmalignant)
none
asymptomatic
symptomatic, requiring therapeutic paracentesis
perforation or abdominal pain, requiring surgery fever, change in or toxic megacolon bowel habits with ileus or peritoneal signs, and radiographic or biopsy documentation Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Melena/GI bleeding, Rectal bleeding/hematochezia, Hypotension. Colitis none abdominal pain with mucus and/or blood in stool Constipation none requiring stool softener or dietary modication requiring laxatives obstipation requiring manual evacuation or enema requiring IV uid replacement (sustained) obstruction or toxic megacolon
Dehydration
none
dry mucous membranes and/or diminished skin turgor
requiring IV uid replacement (brief)
physiologic consequences requiring intensive care; hemodynamic collapse
Also consider Diarrhea, Vomiting, Stomatitis/pharyngitis (oral/pharyngeal mucositis), Hypotension. Diarrhea patients without colostomy: none increase of 4 stools/ day over pretreatment increase of 46 stools/ day, or nocturnal stools increase of 7 stools/day or incontinence; or need for parenteral support for dehydration severe increase in loose, watery colostomy output compared with pretreatment, interfering with normal activity physiologic consequences requiring intensive care; or hemodynamic collapse physiologic consequences, requiring intensive care; or hemodynamic collapse
patients with a colostomy:
none
mild increase in loose, watery colostomy output compared with pretreatment
moderate increase in loose, watery colostomy output compared with pretreatment, but not interfering with normal activity
A. TROTTI et al.
29
Grade Adverse Event Diarrhea associated with graft versus host disease (GVHD) for BMT studies, if specied in the protocol. For pediatric BMT studies, if specied in the protocol. None 0 1 500 1000 mL of diarrhea/day 2 1000 1500 mL of diarrhea/day 3 1500 mL of diarrhea/day 4 severe abdominal pain with or without ileus
5 10 mL/kg of diarrhea/day
10 15 mL/kg of diarrhea/day
15 mL/kg of diarrhea/day
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Pain, Dehydration, Hypotension. Duodenal ulcer (requires radiographic or endoscopic documentation) none requiring medical management or nonsurgical treatment uncontrolled by outpatient medical management; requiring hospitalization severe dysphagia, requiring IV hydration perforation or bleeding, requiring emergency surgery
Dyspepsia/heartburn none Dysphagia, esophagitis, odynophagia (painful swallowing) none
mild mild dysphagia, but can eat regular diet
moderate dysphagia, requiring predominantly pureed, soft, or liquid diet
complete obstruction (cannot swallow saliva) requiring enteral or parenteral nutritional support, or perforation
Note: If the adverse event is radiation-related, grade either under Dysphagiaesophageal related to radiation or Dysphagiapharyngeal related to radiation. Dysphagia esophageal related to radiation none mild dysphagia, but can eat regular diet dysphagia, requiring predominantly pureed, soft, or liquid diet Dysphagia, requiring feeding tube, IV hydration or hyperalimentation complete obstruction (cannot swallow saliva); ulceration with bleeding not induced by minor trauma or abrasion or perforation
Also consider Pain due to radiation, Mucositis due to radiation. Note: Fistula is graded separately as Fistulaesophageal. Dysphagia pharyngeal related to radiation none mild dysphagia, but can eat regular diet dysphagia, requiring predominantly pureed, soft, or liquid diet dysphagia, requiring feeding tube, IV hydration or hyperalimentation complete obstruction (cannot swallow saliva); ulceration with bleeding not induced by minor trauma or abrasion or perforation
Also consider Pain due to radiation, Mucositis due to radiation. Note: Fistula is graded separately as Fistulapharyngeal. Fistulaesophageal none Fistulaintestinal Fistularectal/ anal Flatulence none none none mild Fistulapharyngeal none moderate present present present present requiring surgery requiring surgery requiring surgery requiring surgery
30
Biology
Physics
Grade Adverse Event Gastric ulcer (requires radiographic or endoscopic documentation) none 0 1 2 requiring medical management or nonsurgical treatment 3 4
perforation or bleeding without bleeding, requiring perforation, emergency surgery uncontrolled by outpatient medical management; requiring hospitalization or surgery Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia. life-threatening uncontrolled by bleeding, requiring outpatient emergency surgery medical management; requiring hospitalization or surgery Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia. Gastritis none requiring medical management or nonsurgical treatment Hematemesis is graded in the HEMORRHAGE category. Hematochezia is graded in the HEMORRHAGE category as Rectal bleeding/hematochezia. Ileus (or neuroconstipation) Mouth dryness Mucositis Notes: Mucositis not due to radiation is graded in the GASTROINTESTINAL category for specic sites: Colitis, Esophagitis, Gastritis, Stomatitis/pharyngitis (oral/pharyngeal mucositis), and Typhlitis; or the RENAL/GENITOURINARY category for Vaginitis. Radiation-related mucositis is graded as Mucositis due to radiation. Mucositis due to radiation none erythema of the mucosa patchy pseudomembranous reaction (patches generally 1.5 cm in diameter and noncontiguous) conuent pseudomembranous reaction (contiguous patches generally 1.5 cm in diameter) necrosis or deep ulceration; may include bleeding not induced by minor trauma or abrasion none intermittent, not requiring intervention moderate requiring nonsurgical intervention requiring surgery
normal
mild
Also consider Pain due to radiation. Notes: Grade radiation mucositis of the larynx here. Dysphagia related to radiation is also graded as either Dysphagiaesophageal related to radiation or Dysphagia-pharyngeal related to radiation, depending on the site of treatment. Nausea none able to eat oral intake signicantly decreased no signicant intake, requiring IV uids abdominal pain with pancreatic enzyme elevation
Pancreatitis
none
complicated by shock (acute circulatory failure)
Also consider Hypotension. Note: Amylase is graded in the METABOLIC/LABORATORY category. Pharyngitis is graded in the GASTROINTESTINAL category as Stomatitis/pharyngitis (oral/pharyngeal mucositis).
A. TROTTI et al.
31
Grade Adverse Event Proctitis none 0 1 increased stool frequency, occasional blood-streaked stools or rectal discomfort (including hemorrhoids) not requiring medication 2 increased stool frequency, bleeding, mucus discharge, or rectal discomfort requiring medication; anal ssure 3 4
perforation, bleeding increased stool or necrosis or other frequency/diarrhea life-threatening requiring complication parenteral requiring surgical support; rectal intervention (e.g., bleeding colostomy) requiring transfusion; or persistent mucus discharge, necessitating pads Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Pain due to radiation. Notes: Fistula is graded separately as Fistularectal/anal. Proctitis occurring more than 90 days after the start of radiation therapy is graded in the RTOG/EORTC Late Radiation Morbidity Scoring Scheme. (See Appendix IV) Salivary gland changes none slightly thickened saliva; may have slightly altered taste (e.g., metallic); additional uids may be required slightly altered painless ulcers, erythema, or mild soreness in the absence of lesions painless ulcers, erythema, or mild soreness in the absence of lesions thick, ropy, sticky saliva; markedly altered taste; alteration in diet required acute salivary gland necrosis
Sense of smell Stomatitis/ pharyngitis (oral/pharyngeal mucositis)
normal none
markedly altered painful erythema, edema, or ulcers, but can eat or swallow
painful erythema, edema, or ulcers requiring IV hydration
severe ulceration or requires parenteral or enteral nutritional support or prophylactic intubation severe ulceration requiring prophylactic intubation or resulting in documented aspiration pneumonia
none
painful erythema, edema or ulcers but can swallow
painful erythema, edema, or ulcers preventing swallowing or requiring hydration or parenteral (or enteral) nutritional support
Note: Radiation-related mucositis is graded as Mucositis due to radiation. Taste disturbance (dysgeusia) Typhlitis (inammation of the cecum) normal slightly altered markedly altered
perforation, bleeding or necrosis or other life-threatening complication requiring surgical intervention (e.g., colostomy) Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Hypotension, Febrile neutropenia.
none
abdominal pain, diarrhea, fever, and radiographic or biopsy documentation
32
Biology
Physics
Grade Adverse Event Vomiting none 0 1 1 episode in 24 hours over pretreatment 2 25 episodes in 24 hours over pretreatment 3 6 episodes in 24 hours over pretreatment; or need for IV uids 4 requiring parenteral nutrition; or physiologic consequences requiring intensive care; hemodynamic collapse
Also consider Dehydration. Weight gain is graded in the CONSTITUTIONAL SYMPTOMS category. Weight loss is graded in the CONSTITUTIONAL SYMPTOMS category. Gastrointestinal Other (Specify, ) none mild moderate severe life-threatening or disabling
HEMORRHAGE Notes: Transfusion in this section refers to pRBC infusion. For any bleeding with grade 3 or 4 platelets ( 50,000), always grade Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia. Also consider Platelets, Transfusion: pRBCs, and Transfusion: platelets in addition to grading severity by grading the site or type of bleeding. If the site or type of Hemorrhage/bleeding is listed, also use the grading that incorporates the site of bleeding: CNS Hemorrhage/ bleeding, Hematuria, Hematemesis, Hemoptysis, Hemorrhage/bleeding with surgery, Melena/lower GI bleeding, Petechiae/purpura (Hemorrhage/bleeding into skin), Rectal bleeding/hematochezia, Vaginal bleeding. If the platelet count is 50,000 and the site or type of bleeding is listed, grade the specic site. If the site or type is not listed and the platelet count is 50,000, grade Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia and specify the site or type in the OTHER category. Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia none mild without transfusion requiring transfusion catastrophic bleeding, requiring major nonelective intervention
Also consider Platelets, Hemoglobin, Transfusion: platelets, Transfusion: pRBCs, site or type of bleeding. If the site is not listed, grade as HemorrhageOther (Specify site, ). Note: This adverse event must be graded for any bleeding with grade 3 or 4 thrombocytopenia. Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia none mild without transfusion requiring transfusion catastrophic bleeding requiring major nonelective intervention ).
Also consider Platelets, Hemoglobin, Transfusion: platelets, Transfusion: pRBCs, HemorrhageOther (Specify site,
Note: Bleeding in the absence of grade 3 or 4 thrombocytopenia is graded here only if the specic site or type of bleeding is not listed elsewhere in the HEMORRHAGE category. Also grade as Other in the HEMORRHAGE category. CNS hemorrhage/ bleeding none bleeding noted on CT or other scan with no clinical consequences hemorrhagic stroke or hemorrhagic vascular event (CVA) with neurologic signs and symptoms catastrophic bleeding, requiring major nonelective intervention catastrophic bleeding, requiring major nonelective intervention
Epistaxis
none
mild without transfusion
requiring transfusion
Hematemesis
none
A. TROTTI et al.
33
Grade Adverse Event Hematuria (in the absence of vaginal bleeding) none 0 1 microscopic only 2 intermittent gross bleeding, no clots 3 persistent gross bleeding or clots; may require catheterization or instrumentation, or transfusion requiring transfusion 4 open surgery or necrosis or deep bladder ulceration
Hemoptysis
none
catastrophic bleeding, requiring major nonelective intervention catastrophic bleeding, requiring major nonelective intervention
Hemorrhage/bleeding associated with surgery
none
Note: Expected blood loss at the time of surgery is not graded as an adverse event. Melena/GI bleeding none mild without transfusion requiring transfusion catastrophic bleeding, requiring major nonelective intervention
Petechiae/purpura none (hemorrhage/bleeding into skin or mucosa) Rectal bleeding/ hematochezia none
rare petechiae of skin
petechiae or purpura in dependent areas of skin
generalized petechiae or purpura of skin or petechiae of any mucosal site requiring transfusion
mild without transfusion or medication
persistent, requiring medication (e.g., steroid suppositories) and/ or break from radiation treatment requiring 2 pads per day, but not requiring transfusion
catastrophic bleeding, requiring major nonelective intervention
Vaginal bleeding
none
spotting, requiring 2 pads per day
catastrophic bleeding, requiring major nonelective intervention catastrophic bleeding, requiring major nonelective intervention ULN 20.0 ULN
HemorrhageOther (Specify site, )
none
HEPATIC Alkaline phosphatase WNL ULN2.5 ULN ULN1.5 ULN 2 3 mg/100 mL 2.55.0 ULN 5.020.0
Bilirubin
WNL
1.53.0
ULN
3.010.0
ULN
10.0
ULN
Bilirubin associated with graft versus host disease (GVHD) for BMT studies, if specied in the protocol. GGT ( -Glutamyl transpeptidase)
normal
3 6 mg/100 mL
6 15 mg/ 100 mL
15 mg/100 mL
WNL
ULN2.5 ULN
2.55.0
ULN
5.020.0
ULN
20.0
ULN
34
Biology
Physics
Grade Adverse Event Hepatic enlargement 0 absent 1 2 present 3 4
Note: Grade Hepatic enlargement only for treatment-related adverse event including veno-occlusive disease. Hypoalbuminemia Liver dysfunction/failure (clinical) Portal vein ow SGOT (AST) (serum glutamic oxaloacetic transaminase) SGPT (ALT) (serum glutamic pyruvic transaminase) HepaticOther (Specify, ) Catheter-related infection WNL normal LLN3 g/dL 2 3 g/dL 2 g/dL asterixis encephalopathy or coma 20.0 ULN
normal WNL
ULN2.5 ULN
decreased portal vein ow 2.55.0 ULN
reversal/retrograde portal vein ow 5.020.0 ULN
WNL
ULN2.5
ULN
2.55.0
ULN
5.020.0
ULN
20.0
ULN
none
mild
moderate
severe
INFECTION/FEBRILE NEUTROPENIA none mild, no active treatment moderate, localized infection, requiring local or oral treatment severe, systemic infection, requiring IV antibiotic or antifungal treatment or hospitalization present life-threatening sepsis (e.g., septic shock)
Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection) (ANC 1.0 109/L, fever 38.5C)
none
life-threatening sepsis (e.g., septic shock)
Also consider Neutrophils. Note: Hypothermia instead of fever may be associated with neutropenia and is graded here. none present Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia (ANC 1.0 109/L) Also consider Neutrophils. Note: Hypothermia instead of fever may be associated with neutropenia and is graded here. life-threatening sepsis (e.g., septic shock)
In the absence of documented infection grade 3 or 4 neutropenia with fever is graded as Febrile neutropenia. Infection with none present life-threatening sepsis unknown ANC (e.g., septic shock) Note: This adverse event criterion is used in the rare case when ANC is unknown.
A. TROTTI et al.
35
Grade Adverse Event Infection without neutropenia none 0 1 mild, no active treatment 2 moderate, localized infection, requiring local or oral treatment 3 severe, systemic infection, requiring IV antibiotic or antifungal treatment, or hospitalization 4 life-threatening sepsis (e.g., septic shock)
Also consider Neutrophils. Wound-infectious is graded in the DERMATOLOGY/SKIN category. Infection/Febrile Neutropenia Other (Specify, ) none mild moderate severe life-threatening or disabling
LYMPHATICS Lymphatics normal mild lymphedema moderate lymphedema requiring compression; lymphocyst severe lymphedema limiting function; lymphocyst requiring surgery severe severe lymphedema limiting function with ulceration
LymphaticsOther (Specify, )
none
mild
moderate
METABOLIC/LABORATORY Acidosis (metabolic or respiratory) normal pH normal, but 7.3 pH 7.3 pH 7.3 with lifethreatening physiologic consequences pH 7.5 with lifethreatening physiologic consequences ULN ULN 5.0 10 ULN ULN 8 mEq/dL
Alkalosis (metabolic or respiratory)
normal
pH
normal, but 7.5
pH
7.5
Amylase Bicarbonate CPK (creatine phosphokinase) Hypercalcemia Hypercholesterolemia
WNL WNL WNL WNL WNL
ULN1.5 ULN2.5
ULN ULN
1.52.0 2.55
ULN ULN
2.05.0 510
LLN16 mEq/dL
1115 mEq/dL
810 mEq/dL
ULN11.5 mg/dL ULN2.9 mmol/L ULN300 mg/dL ULN7.75 mmol/L ULN160 mg/dL ULN8.9 mmol/L ULN5.5 mmol/L ULN3.0 mg/dL ULN1.23 mmol/L ULN150 mmol/L ULN2.5 ULN
11.512.5 mg/dL 2.93.1 mmol/L 300400 mg/dL 7.7510.34 mmol/L 160250 mg/dL 8.913.9 mmol/L 5.56.0 mmol/L 150155 mmol/L 2.55.0 ULN
12.513.5 mg/dL 3.13.4 mmol/L 400500 mg/dL 10.3412.92 mmol/L 250500 mg/dL 13.927.8 mmol/L 6.07.0 mmol/L 3.08.0 mg/dL 1.233.30 mmol/L 155160 mmol/L 5.010 ULN
13.5 mg/dL 3.4 mmol/L 500 mg/dL 12.92 mmol/L 500 mg/dL 27.8 mmol/L or acidosis 7.0 mmol/L 8.0 mg/dL 3.30 mmol/L 160 mmol/L 10 ULN
Hyperglycemia
WNL
Hyperkalemia Hypermagnesemia Hypernatremia Hypertriglyceridemia
WNL WNL WNL WNL
36
Biology
Physics
Grade Adverse Event Hyperuricemia WNL 0 1 2 3 ULN 10 mg/dL 0.59 mmol/L with physiologic consequences 4 10 mg/dL 0.59 mmol/L
ULN 10 mg/dL 0.59 mmol/L without physiologic consequences Also consider Tumor lysis syndrome, Renal failure, Creatinine, Hyperkalemia. Hypocalcemia Hypoglycemia Hypokalemia Hypomagnesemia Hyponatremia Hypophosphatemia WNL WNL WNL WNL WNL WNL LLN8.0 mg/dL LLN2.0 mmol/L LLN55 mg/dL LLN3.0 mmol/L LLN3.0 mmol/L LLN1.2 mg/dL LLN0.5 mmol/L LLN130 mmol/L LLN2.5 mg/dL LLN0.8 mmol/L ULN1.5 mild ULN 7.0 8.0 mg/dL 1.75 2.0 mmol/L 40 55 mg/dL 2.2 3.0 mmol/L 0.9 1.2 mg/dL 0.4 0.5 mmol/L 2.0 2.5 mg/dL 0.6 0.8 mmol/L 1.52.0 moderate ULN
6.0 7.0 mg/dL 1.5 1.75 mmol/L 30 40 mg/dL 1.7 2.2 mmol/L 2.5 3.0 mmol/L 0.7 0.9 mg/dL 0.3 0.4 mmol/L 120 130 mmol/L 1.0 2.0 mg/dL 0.3 0.6 mmol/L 2.05.0 severe ULN
6.0 mg/dL 1.5 mmol/L 30 mg/dL 1.7 mmol/L 2.5 mmol/L 0.7 mg/dL 0.3 mmol/L 120 mmol/L 1.0 mg/dL 0.3 mmol/L 5.0 ULN
Hypothyroidism is graded in the ENDOCRINE category. Lipase WNL Metabolic/Laboratory none Other (Specify, ) life-threatening or disabling
MUSCULOSKELETAL Arthralgia is graded in the PAIN category. Arthritis none mild pain with inammation, erythema or joint swelling but not interfering with function asymptomatic with weakness on physical exam moderate pain with inammation, erythema, or joint swelling interfering with function, but not interfering with activities of daily living disabling severe pain with inammation, erythema, or joint swelling and interfering with activities of daily living
Muscle weakness (not due to neuropathy)
normal
symptomatic and interfering symptomatic and bedridden or with function, but not interfering with disabling interfering with activities activities of daily of daily living living
Myalgia [tenderness or pain in muscles] is graded in the PAIN category. Myositis none (inammation/ damage of muscle) Also consider CPK. Note: Myositis implies muscle damage (i.e., elevated CPK). Osteonecrosis (avascular necrosis) Musculoskeletal Other (Specify, ) none asymptomatic and detected by imaging only mild symptomatic and interfering symptomatic and symptomatic; or with function, but not interfering with disabling interfering with activities activities of daily of daily living living moderate severe life-threatening or disabling mild pain, not interfering with function pain interfering with function, but not interfering with activities of daily living pain interfering bedridden or with function disabling and interfering with activities of daily living
none
A. TROTTI et al.
37
Grade Adverse Event 0 1 2 NEUROLOGY Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category. Arachnoiditis/ meningismus/ radiculitis absent mild pain not interfering with function moderate pain interfering with function, but not interfering with activities of daily living mild symptoms interfering with function, but not interfering with activities of daily living severe pain interfering with activities of daily living unable to function or perform activities of daily living; bedridden; paraplegia 3 4
Also consider Headache, Vomiting, Fever. Ataxia (incoordination) normal asymptomatic but abnormal on physical exam, and not interfering with function moderate symptoms interfering with activities of daily living transient ischemic event or attack (TIA) bedridden or disabling
CNS cerebrovascular ischemia
none
permanent event (e.g., cerebral vascular accident)
CNS hemorrhage/bleeding is graded in the HEMORRHAGE category. Cognitive none disturbance/learning problems cognitive disability; not interfering with work/school performance; preservation of intelligence cognitive disability; interfering with work/school performance; decline of 1 SD (Standard Deviation) or loss of developmental milestones confusion or disorientation or attention decit interfering with function, but not interfering with activities of daily living cognitive disability; resulting in signicant impairment of work/school performance; cognitive decline 2 SD inability to work/frank mental retardation
Confusion
normal
confusion or disorientation or attention decit of brief duration; resolves spontaneously with no sequelae
confusion or delirium interfering with activities of daily living
harmful to others or self; requiring hospitalization
Cranial neuropathy is graded in the NEUROLOGY category as Neuropathycranial. Delusions Depressed level of consciousness normal normal somnolence or sedation not interfering with function present obtundation or stupor; difcult to arouse; interfering with activities of daily living interfering with activities of daily living toxic psychosis coma
somnolence or sedation interfering with function, but not interfering with activities of daily living Note: Syncope (fainting) is graded in the NEUROLOGY category. Dizziness/ lightheadedness none not interfering with function interfering with function, but not interfering with activities of daily living
bedridden or disabling
Dysphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category.
38
Biology
Physics
Grade Adverse Event Extrapyramidal/ none involuntary movement/restlessness 0 1 mild involuntary movements not interfering with function 2 moderate involuntary movements interfering with function, but not interfering with activities of daily living 3 severe involuntary movements or torticollis interfering with activities of daily living present 4 bedridden or disabling
Hallucinations
normal
toxic psychosis
Headache is graded in the PAIN category. frequent difculty difculty sleeping sleeping, interfering with interfering with function, but not activities of daily interfering with living activities of daily living Note: This adverse event is graded when insomnia is related to treatment. If pain or other symptoms interfere with sleep do NOT grade as insomnia. Insomnia normal occasional difculty sleeping not interfering with function Irritability (children 3 years of age) normal mild; easily consolable moderate; requiring increased attention severe; inconsolable
Leukoencephalopathy none associated radiological ndings
mild increase in SAS (subarachnoid space) and/or mild ventriculomegaly; and/or small ( multiple) focal T2 hyperintensities, involving periventricular white matter or 1/3 of susceptible areas of cerebrum memory loss not interfering with function
moderate increase in SAS; and/or moderate ventriculomegaly; and/or focal T2 hyperintensities extending into centrum ovale; or involving 1/3 to 2/3 of susceptible areas of cerebrum memory loss interfering with function, but not interfering with activities of daily living moderate mood alteration interfering with function, but not interfering with activities of daily living moderate mood alteration interfering with function, but not interfering with activities of daily living moderate mood alteration interfering with function, but not interfering with activities of daily living
severe increase in SAS; severe ventriculomegaly; near total white matter T2 hyperintensities or diffuse low attenuation (CT); focal white matter necrosis (cystic) memory loss interfering with activities of daily living
severe increase in SAS; severe ventriculomegaly; diffuse low attenuation with calcication (CT); diffuse white matter necrosis (MRI)
Memory loss
normal
amnesia
Mood alteration anxiety, agitation
normal
mild mood alteration not interfering with function
severe mood alteration interfering with activities of daily living severe mood alteration interfering with activities of daily living severe mood alteration interfering with activities of daily living
suicidal ideation or danger to self
Mood alteration depression
normal
suicidal ideation or danger to self
Mood alteration euphoria
normal
danger to self
Neuropathic pain is graded in the PAIN category.
A. TROTTI et al.
39
Adverse Event Grade Adverse Event Neuropathy cranial Neuropathy motor 0 absent 1 2 present, not interfering with activities of daily living mild objective weakness interfering with function, but not interfering with activities of daily living objective sensory loss or paresthesia (including tingling), interfering with function, but not interfering with activities of daily living 3 present, interfering with activities of daily living objective weakness interfering with activities of daily living 4 life-threatening, disabling paralysis
normal
subjective weakness but no objective ndings
Neuropathy sensory
normal
loss of deep tendon reexes or paresthesia (including tingling) but not interfering with function
sensory loss or paresthesia interfering with activities of daily living
permanent sensory loss that interferes with function
Nystagmus
absent
present
Also consider Visiondouble vision. Personality/ behavioral normal change, but not disruptive to patient or family disruptive to patient or family disruptive to patient and family; requiring mental health intervention interfering with activities of daily living harmful to others or self; requiring hospitalization
Pyramidal tract dysfunction (e.g., 1 tone, hyperreexia, positive Babinski, 2 ne motor coordination) Seizure(s)
normal
asymptomatic with abnormality on physical examination
symptomatic or interfering with function but not interfering with activities of daily living
bedridden or disabling; paralysis
none
seizure(s) self-limited and consciousness is preserved
seizure(s) in which consciousness is altered
seizures of any type which are prolonged, repetitive, or difcult to control (e.g., status epilepticus, intractable epilepsy) inability to communicate
Speech impairment (e.g., dysphasia or aphasia)
normal
awareness of receptive or expressive dysphasia, not impairing ability to communicate
receptive or expressive dysphasia, impairing ability to communicate
Syncope absent present (fainting) Also consider CARDIOVASCULAR (ARRHYTHMIA), Vasovagal episode, CNS cerebrovascular ischemia.
40
Biology
Physics
Grade Adverse Event Tremor none 0 1 mild and brief or intermittent but not interfering with function 2 moderate tremor interfering with function, but not interfering with activities of daily living interfering with function, but not interfering with activities of daily living moderate 3 severe tremor interfering with activities of daily living 4
Vertigo
none
not interfering with function
interfering with activities of daily living
bedridden or disabling
Neurology Other (Specify, )
none
mild
severe
OCULAR/VISUAL Cataract none asymptomatic symptomatic, partial visual loss symptomatic, visual loss requiring treatment or interfering with function symptomatic and interfering with activities of daily living
Conjunctivitis
none
abnormal ophthalmologic changes, but asymptomatic or symptomatic without visual impairment (i.e., pain and irritation) mild, not requiring treatment increase in intraocular pressure but no visual loss abnormal ophthalmologic changes but asymptomatic or symptomatic without visual impairment (i.e., pain and irritation) mild: not interfering with function
symptomatic and interfering with function, but not interfering with activities of daily living
Dry eye Glaucoma
normal none
moderate or requiring articial tears increase in intraocular pressure with retinal changes symptomatic and interfering with function, but not interfering with activities of daily living
visual impairment
unilateral or bilateral loss of vision (blindness) unilateral or bilateral loss of vision (blindness)
Keratitis (corneal inammation/ corneal ulceration)
none
symptomatic and interfering with activities of daily living
Tearing (watery eyes)
none
moderate: interfering with function, but not interfering with activities of daily living symptomatic and interfering with function, but not interfering with activities of daily living
interfering with activities of daily living
Visionblurred vision
normal
A. TROTTI et al.
41
Grade Adverse Event Visiondouble vision (diplopia) 0 normal 1 2 symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with function, but not interfering with activities of daily living moderate 3 symptomatic and interfering with activities of daily living 4
Visionashing lights/oaters
normal
mild, not interfering with function
Visionnight blindness (nyctalopia)
normal
abnormal electroretinography but asymptomatic
Vision photophobia
normal
Ocular/Visual Other (Specify, )
normal
mild
severe
unilateral or bilateral loss of vision (blindness)
PAIN Abdominal pain or cramping none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling
Arthralgia (joint pain)
none
mild pain not interfering with function
disabling
Arthritis (joint pain with clinical signs of inammation) is graded in the MUSCULOSKELETAL category. Bone pain none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling
42
Biology
Physics
Grade Adverse Event Chest pain (noncardiac and nonpleuritic) none 0 1 mild pain not interfering with function 2 moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain interfering with sexual activity 3 severe pain: pain or analgesics severely interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living severe pain preventing sexual activity disabling 4
Dysmenorrhea
none
disabling
Dyspareunia
none
Dysuria is graded in the RENAL/GENITOURINARY category. Earache (otalgia) none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling
Headache
none
disabling
Hepatic pain
none
disabling
Myalgia (muscle pain)
none
disabling
Neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, postinfectious neuralgia, or painful neuropathies)
none
severe pain: pain or analgesics severely interfering with activities of daily living
disabling
A. TROTTI et al.
43
Grade Adverse Event Pain due to radiation none 0 1 mild pain not interfering with function 2 moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living moderate 3 severe pain: pain or analgesics severely interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling 4
Pelvic pain
none
disabling
Pleuritic pain
none
disabling
Rectal or perirectal pain (proctalgia)
none
disabling
Tumor pain (onset or exacerbation of tumor pain due to treatment)
none
disabling
Tumor are is graded in the SYNDROME category. PainOther (Specify, ) PULMONARY Adult Respiratory Distress Syndrome (ARDS) Apnea Carbon monoxide diffusion capacity (DLCO) Cough absent present none mild severe disabling
none 90% of pretreatment or normal value absent
75 90% of pretreatment or normal value
50 75% of pretreatment or normal value
present 25 50% of pretreatment or normal value
requiring intubation 25% of pretreatment or normal value
mild, relieved by nonprescription medication
requiring narcotic antitussive
severe cough or coughing spasms, poorly controlled or unresponsive to treatment
44
Biology
Physics
Grade Adverse Event Dyspnea (shortness of breath) FEV1 0 normal 1 2 dyspnea on exertion 3 dyspnea at normal level of activity 25 50% of pretreatment or normal value severe, prolonged, and refractory to treatment decreased O2 saturation at rest, requiring supplemental oxygen symptomatic, requiring O2 or therapeutic thoracentesis radiographic changes and requiring oxygen sclerosis or surgery required requiring oxygen 4 dyspnea at rest or requiring ventilator support 25% of pretreatment or normal value
90% of pretreatment or normal value none
75 90% of pretreatment or normal value mild, not requiring treatment
50 75% of pretreatment or normal value moderate, requiring treatment decreased O2 saturation with exercise
Hiccoughs (hiccups, singulitus) Hypoxia
normal
decreased O2 saturation, requiring pressure support (CPAP) or assisted ventilation life-threatening (e.g., requiring intubation)
Pleural effusion (nonmalignant)
none
asymptomatic and not requiring treatment
symptomatic, requiring diuretics
Pleuritic pain is graded in the PAIN category. Pneumonitis/ pulmonary inltrates Pneumothorax none radiographic changes but asymptomatic or symptoms not requiring steroids no intervention required radiographic changes, but asymptomatic or symptoms not requiring steroids radiographic changes and requiring steroids or diuretics chest tube required radiographic changes and requiring assisted ventilation life-threatening
none
Pulmonary embolism is graded as Thrombosis/embolism in the CARDIOVASCULAR (GENERAL) category. Pulmonary brosis none requiring steroids or diuretics requiring assisted ventilation
Note: Radiation-related pulmonary brosis is graded in the RTOG/EORTC Late Radiation Morbidity Scoring Scheme-Lung. (See Appendix IV) Voice changes/ stridor/larynx (e.g., hoarseness, loss of voice, laryngitis) normal mild or intermittent hoarseness persistent hoarseness, but able to vocalize; may have mild to moderate edema whispered speech, not able to vocalize; may have marked edema marked dyspnea/stridor requiring tracheostomy or intubation
Notes: Cough from radiation is graded as cough in the PULMONARY category. Radiation-related hemoptysis from larynx/pharynx is graded as Grade 4 Mucositis due to radiation in the GASTROINTESTINAL category. Radiation-related hemoptysis from the thoracic cavity is graded as Grade 4 Hemoptysis in the HEMORRHAGE category. Pulmonary Other (Specify, ) none mild moderate severe life-threatening or disabling
A. TROTTI et al.
45
Grade Adverse Event 0 1 2 RENAL/GENITOURINARY Bladder spasms absent mild symptoms, not requiring intervention ULN1.5 ULN symptoms requiring antispasmodic 1.53.0 ULN severe symptoms requiring narcotic 3.06.0 ULN 6.0 3 4
Creatinine
WNL
ULN
Note: Adjust to age-appropriate levels for pediatric patients. Dysuria (painful urination) Fistula or GU stula (e.g., vaginal, vesicovaginal) Hemoglobinuria Incontinence none none mild symptoms requiring no intervention symptoms relieved with therapy symptoms not relieved despite therapy requiring intervention
none
requiring surgery
present with coughing, sneezing, etc.
spontaneous, some control injury of bladder with primary repair
no control (in the absence of stula) sepsis, stula, or obstruction requiring secondary surgery; loss of one kidney; injury requiring anastomosis or reimplantation 4 or 3.5 g/24 hours
Hematuria (in the absence of vaginal bleeding) is graded in the HEMORRHAGE category.
Operative injury to bladder and/ or ureter
none
septic obstruction of both kidneys or vesicovaginal stula requiring diversion
Proteinuria
normal or 0.15 g/24 hours
or 0.151.0 g/24 hours
to 3 or 1.03.5 g/24 hours
nephrotic syndrome
Note: If there is an inconsistency between absolute value and dip stick reading, use the absolute value for grading. Renal failure Ureteral obstruction Urinary electrolyte wasting (e.g., Fanconis syndrome, renal tubular acidosis) none none none unilateral, not requiring surgery asymptomatic, not requiring treatment mild, reversible and manageable with oral replacement requiring dialysis, but reversible bilateral, not requiring surgery reversible but requiring IV replacement requiring dialysis and irreversible stent, nephrostomy tube, or surgery irreversible, requiring continued replacement
Also consider Acidosis, Bicarbonate, Hypocalcemia, Hypophosphatemia. Urinary frequency/ urgency normal increase in frequency or nocturia up to 2 normal increase 2 normal but hourly hourly or more with urgency, or requiring catheter
46
Biology
Physics
Grade Adverse Event Urinary retention 0 normal 1 hesitancy or dribbling, but no signicant residual urine; retention occurring during the immediate postoperative period 2 hesitancy requiring medication or occasional in/out catheterization ( 4 per week), or operative bladder atony requiring indwelling catheter beyond immediate postoperative period but for 6 weeks 3 requiring frequent in/out catheterization ( 4 per week) or urological intervention (e.g., TURP, suprapubic tube, urethrotomy) 4 bladder rupture
Urine color change (not related to other dietary or physiologic cause e.g., bilirubin, concentrated urine, hematuria) Vaginitis (not due to infection) Renal/ Genitourinary Other (Specify, ) Secondary Malignancy Other (Specify type, ) excludes metastasis from initial primary
normal
asymptomatic, change in urine color
Vaginal bleeding is graded in the HEMORRHAGE category. none mild, not requiring treatment moderate, relieved with treatment severe, not relieved with treatment, or ulceration not requiring surgery severe ulceration requiring surgery
none
mild
moderate
SECONDARY MALIGNANCY none present
SEXUAL/REPRODUCTIVE FUNCTION Dyspareunia is graded in the PAIN category. Dysmenorrhea is graded in the PAIN category. Erectile impotence normal mild (erections impaired but satisfactory) moderate (erections impaired, unsatisfactory for intercourse) no erections
Female sterility
normal
sterile
Feminization of male is graded in the ENDOCRINE category. Irregular menses (change from baseline) normal occasionally irregular or lengthened interval, but continuing menstrual cycles very irregular, but continuing menstrual cycles persistent amenorrhea
A. TROTTI et al.
47
Grade Adverse Event Libido Male infertility 0 normal 1 decrease in interest 2 severe loss of interest oligospermia (low sperm count) requiring treatment and/or interfering with sexual function, dyspareunia moderate severe 3 azoospermia (no sperm) 4
Masculinization of female is graded in the ENDOCRINE category. Vaginal dryness normal mild
Sexual/Reproductive none Function Other (Specify, )
mild
disabling
SYNDROMES (not included in previous categories) Acute vascular leak syndrome is graded in the CARDIOVASCULAR (GENERAL) category. ARDS (Adult Respiratory Distress Syndrome) is graded in the PULMONARY category. Autoimmune reactions are graded in the ALLERGY/IMMUNOLOGY category. DIC (disseminated intravascular coagulation) is graded in the COAGULATION category. Fanconis syndrome is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category. Renal tubular acidosis is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category. Stevens-Johnson syndrome (erythema multiforme) is graded in the DERMATOLOGY/SKIN category. SIADH (syndrome of inappropriate antidiuretic hormone) is graded in the ENDOCRINE category. Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura/TTP or hemolytic uremic syndrome/HUS) is graded in the COAGULATION category. Tumor are none mild pain not interfering with function moderate pain; pain or analgesics interfering with function, but not interfering with activities of daily living severe pain; pain or analgesics interfering with function and interfering with activities of daily living Disabling
Also consider Hypercalcemia. Note: Tumor are is characterized by a constellation of symptoms and signs in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The symptoms/signs include tumor pain, inammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances. Tumor lysis absent syndrome Also consider Hyperkalemia, Creatinine. present
Urinary electrolyte wasting (e.g., Fanconis syndrome, renal tubular acidosis) is graded in the RENAL/GENITOURINARY category. Syndromes Other (Specify, ) none mild moderate severe life-threatening or disabling

Science

Hochgeladen von

Dokumentinformationen

Originalbeschreibung:

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

Science

Hochgeladen von

Copyright:

Verfügbare Formate

Int. J. Radiation Oncology Biol. Phys., Vol. 47, No. 1, pp.

Volume 47, Number 1, 2000

Impact of Common Toxicity Criteria v. 2.0 on radiotherapy

Volume 47, Number 1, 2000

APPENDIX A COMMON TOXICITY CRITERIA (CTC)

Allergy/ ImmunologyOther (Specify, )

Volume 47, Number 1, 2000

Auditory/ HearingOther (Specify, )

Impact of Common Toxicity Criteria v. 2.0 on radiotherapy

LLN1.0 109/L LLN1000/mm3 75 100% LLN

0.5 1.0 109/L 500 1000/mm3 50 75% LLN

0.5 109/L 500/mm3 25 50% LLN

LLN75.0 109/L LLN75,000/mm3

10.0 109/L 10,000/mm3

For BMT studies, if specied in the protocol.

50.0 75.0 109/L 50,000 75,000/ mm3

10.0 109/L 10,000/mm3

Volume 47, Number 1, 2000

For BMT studies, if specied in the protocol.

1 platelet transfusion in 24 hours

2 platelet transfusions in 24 hours

3 platelet transfusions in 24 hours

For pediatric BMT studies, if specied in the protocol.

15 mL/kg in 24 hours elective or planned

15 30 mL/kg in 24 hours elective or planned

Impact of Common Toxicity Criteria v. 2.0 on radiotherapy

Grade Adverse Event 0 1 2 3 4

Nodal/junctional arrhythmia/ dysrhythmia

asymptomatic, not requiring treatment

symptomatic, but not requiring treatment

life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock)

symptomatic and requiring treatment

asymptomatic, not requiring treatment

symptomatic, but not requiring treatment

symptomatic and requiring treatment

asymptomatic, not requiring treatment

symptomatic, but not requiring treatment

Supraventricular arrhythmias (SVT/atrial brillation/ utter)

asymptomatic, not requiring treatment

symptomatic, but not requiring treatment

life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock)

asymptomatic, not requiring treatment

life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock)

asymptomatic, not requiring treatment

symptomatic, but not requiring treatment

symptomatic, and requiring treatment of underlying cause

life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock)

Volume 47, Number 1, 2000

Grade Adverse Event 0 1 2 3 4

Cardiac left ventricular function

severe or refractory CHF or requiring intubation

Cardiac troponin T (cTnT) Edema

0.03 0.05 ng/ mL asymptomatic, not requiring therapy

0.05 0.1 ng/mL symptomatic, requiring therapy

Impact of Common Toxicity Criteria v. 2.0 on radiotherapy

Pericardial none effusion/pericarditis

Peripheral arterial ischemia

requiring surgical intervention

deep vein thrombosis, requiring anticoagulant therapy requiring surgical intervention

embolic event including pulmonary embolism

Cardiovascular/ GeneralOther (Specify, )

0.25 0.5 LLN 40 70% decrease from pretreatment value or LLN

20 40% decrease from pretreatment value or LLN