COMMON TOXICITY
`CRITERIA MANUAL
`
`Common Toxicity Criteria, Version 2.0
`June 1, 1999
`
`NCI CTEP Help Desk -
`Telephone: (301) 840-8202
`Fax: (301) 948-2242
`E-mail: ncictephelp@ctep.nci.nih.gov
`
`AVENTIS EXHIBIT 2229
`Mylan v. Aventis IPR2016-00712
`
`

`
`Table of Contents
`COMMON TOXICITY CRITERIA QUICK REFERENCE .......................................................... 1
`1
`INTRODUCTION..................................................................................................................... 5
`1.1
`Purpose of this Manual................................................................................................. 5
`1.2 Making the Entire CTC Available to those Responsible for
`Grading Adverse Events .............................................................................................. 5
`1.3 Defining Adverse Event............................................................................................... 5
`1.4
`Specificity of the CTC ................................................................................................. 6
`2 ORGANIZATION OF THE CTC............................................................................................. 6
`2.1 Adverse Event Categories in the Revised CTC ........................................................... 6
`2.2 Adverse Event Listings ................................................................................................ 7
`2.3 Grades of Adverse Events............................................................................................ 7
`2.4 Adverse Events Not Included in the CTC.................................................................... 8
`2.5 Where to Find Adverse Events from the 1982 Version of the CTC ............................ 8
`2.6 Highlights of Important Changes ................................................................................. 9
`2.7 Appendices to the CTC .............................................................................................. 10
`3 HOW TO GRADE ADVERSE EVENTS .............................................................................. 11
`3.1 What Not to Grade ..................................................................................................... 11
`3.2 Attribution of Causality.............................................................................................. 11
`3.3 Grading at Baseline.................................................................................................... 12
`3.4 Documenting Related Adverse Events....................................................................... 12
`3.5 Grading Adverse Events ............................................................................................ 17
`3.6
`Syndromes.................................................................................................................. 18
`3.7 Dose-limiting Adverse Event..................................................................................... 18
`SUPPLEMENTARY FORMS ................................................................................................ 19
`4.1 Adverse Event Module............................................................................................... 19
`4.2
`Infection Module........................................................................................................ 19
`5 GRADING TOXICITIES IN SPECIAL POPULATIONS..................................................... 19
`5.1 Leukemia Special Adverse Event Criteria ................................................................. 19
`5.2 Bone Marrow/Stem Cell Transplant .......................................................................... 20
`5.3
`Pediatric Adverse Event Criteria................................................................................ 20
`6 RADIATION THERAPY TOXICITIES ................................................................................ 21
`6.1 Acute Radiation Adverse Event ................................................................................. 21
`6.2 Late Radiation Effects................................................................................................ 22
`7 MULTIMODALITY THERAPIES ........................................................................................ 23
`7.1 Grading Adverse Events in Multimodality Therapies when Options are Available .. 23
`8 HARMONIZATION WITH THE INTERNATIONAL MEDICAL TERMINOLOGY ........ 23
`9 CTC USER TOOLS................................................................................................................ 24
`Appendix I: REVISION OF THE COMMON TOXICITY CRITERIA .................................... 25
`COMMON TOXICITY CRITERIA QUICK REFERENCE GUIDE
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`COMMON TOXICITY CRITERIA QUICK REFERENCE
`Definition of Adverse Event
`• Toxicity – Toxicity is NOT clearly defined by regulatory organizations. Toxicity
`has been described as an adverse event that has an attribution (the relationship to
`investigational agent) of possible, probable or definite. To minimize confusion,
`the NCI would recommend that the term toxicity NOT be utilized.
`Note: The Cancer Therapy Evaluation Program, Common Toxicity Criteria,
`Version 2.0 (CTC, v2.0) uses the term “toxicity” for historical reasons, but
`recommends that the term “adverse event” with its attribution be used instead
`whenever possible.
`• Adverse Event – Any unfavorable symptom, sign, or disease (including an
`abnormal laboratory finding) temporally associated with the use of a medical
`treatment or procedure that may or may NOT be considered related to the medical
`treatment or procedure.
`• Common Toxicity Criteria (CTC)1 – The CTC, v2.0 provides descriptive
`terminology for adverse event reporting. A grading (severity) scale is provided
`for each adverse event term.
`Common Toxicity Criteria (CTC) Categories
`• CTC, v2.0 contains 24 categories.
`• CTC, v2.0 is organized by pathophysiology and anatomy.
`• Alphabetical listings of adverse events are placed within categories.
`• The entire CTC, v2.0 should always be available for grading adverse events;
`however, NCI only requires grading of adverse events that occur.
`Changes to the CTC, v2.0
`Major changes in the new version of the CTC, v2.0 are outlined in Sections 2.4 and 2.5 of
`this manual.
`
`
`1 All studies reviewed and approved after March 5, 1998 must utilize the CTC version 2.0 standards 1998
`for adverse event grading and attribution.
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`Grades (General Definitions)
`• 0 = No adverse event or within normal limits
`• 1 = Mild adverse event
`• 2 = Moderate adverse event
`• 3 = Severe and undesirable adverse event
`• 4 = Life-threatening or disabling adverse event
`• 5 = Death related to adverse event
`
`•
`
`The definition of Dose-limiting adverse event is determined by the protocol and not
`by the CTC.
`Grading Adverse Events
`• Any treatment-related adverse event experienced by a patient is graded using the
`specific adverse event terms listed in the CTC, v2.0.
`• Grading is not modified based on a patient’s condition at baseline. Whenever
`possible, baseline data, including laboratory data and signs and symptoms noted
`at study entry, should be collected within the institution as course 0, although at
`present, there is no electronic reporting capability for baseline data within the
`Clinical Data Update System (CDUS).
`If a given adverse event is experienced more than once during a cycle, only the
`grade associated with the most severe adverse event is reported.
`• Syndromes are graded only when diagnosed by a physician; notes within the
`CTC, v2.0 provide guidelines to determine when to grade components of each
`syndrome.
`• Adverse events not included in the CTC, v2.0 should be reported and graded
`under the “Other” adverse event within the appropriate category and graded 1 to 5
`according to the general grade definitions provided above.
`• Several adverse events contain notes reminding the investigator of other related
`adverse events that may occur in association and should be considered for
`grading.
`• Multimodality Therapies – Most adverse events and grading criteria are
`applicable to any treatment modality. Some are specified for a particular
`modality. The most relevant adverse event should be used to grade adverse
`events. When it is not possible to determine whether one or both contributed, use
`the most relevant description of the adverse event.
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`Scale for Attribution of Adverse Event
`
`Assign attribution of each adverse event reported in an NCI-sponsored IND study using
`the following criteria:
`
`ATTRIBUTION OF ADVERSE EVENTS
`Code Descriptor
`5
`Definite
`
`Definition
`The adverse event is clearly related to the investigational
`agent(s)
`The adverse event is likely related to the investigational agent(s)
`The adverse event may be related to the investigational agent(s)
`The adverse event is doubtfully related to the investigational
`agent(s)
`The adverse event is clearly not related to the investigational
`agent(s)
`
`4
`3
`2
`
`1
`
`Probable
`Possible
`Unlikely
`
`Unrelated
`
`What not to Grade
`• Disease progression or signs and symptoms definitely related to disease should
`not be graded. Objective documentation of progression should always be sought.
`• Treatment delivery system malfunctions should not be graded as adverse events.
`Options for More Detailed Reporting
`
`When required by the protocol, additional information may be collected using two special
`modules:
`• Adverse Event Module
`•
`Infections Module
`Populations and Modalities
`When selecting which criteria to use for an adverse event, use the one most consistent
`with the patient population or treatment modality.
`Special criteria for pediatric populations and bone marrow transplant, leukemia, and
`radiation treatment modalities are shaded in the CTC, v2.0 for easy recognition.
`Special Populations
`• Pediatrics – Adverse events and adverse event criteria relevant only to
`children are identified by italic type for easy recognition.
`Treatment Modalities
`• Bone Marrow Transplant Adverse Events – Specialized criteria are included
`for grading Leukocytes, Platelets, Transfusion: platelets, Transfusion: pRBCs,
`Weight gain-Veno Occlusive Disease (VOD), Bilirubin-Graft Versus Host
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`Disease (GVHD), and Stomatitis/pharyngitis for bone marrow transplant, but
`their use must be designated in the protocol.
`• An appendix for grading BMT-related complex/multicomponent events is
`available in the CTC, v2.0.
`• Special grading criteria that may be more pertinent to leukemia, but that
`require calculations, are available for grading Hemoglobin (Hgb),
`Neutrophils, Platelets, and Fibrinogen for leukemia studies, but their use must
`be designated in the protocol.
`• Radiation therapy adverse events are subdivided by time of onset.
`• Acute Radiation Effects (day 1 through day 90) are
`included in the main listing of adverse events.
`• Late Radiation Effects ( all effects seen after 90 days from
`the beginning of radiation therapy are considered late
`effects) developed by RTOG and EORTC are in Appendix
`IV of the CTC, v2.0.
`
`Questions and Comments:
`
`If you have any questions or comments regarding the Common Toxicity Criteria,
`Version 2.0, please contact the NCI CTEP Help Desk by telephone (301) 840-
`8202, fax (301) 948-2242, or E-mail at ncictephelp@ctep.nci.nih.gov.
`Additional information regarding the Common Toxicity Criteria is available on the CTEP
`Home Page (http://ctep.info.nih.gov). Other Common Toxicity Criteria information
`available from the CTEP Home Page:
`•
`Interactive CTC Application
`• Download and print CTC, v2.0
`• CTC Index
`• CTC Manual
`• Generic CTC Data Collection Form
`•
`Instructional CTC Slide Presentation
`
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`1. INTRODUCTION
`The National Cancer Institute (NCI) Common Toxicity Criteria (CTC) were developed in
`1982 for use in adverse drug experience reporting, study adverse event summaries,
`Investigational New Drug (IND) reports to the Food and Drug Administration (FDA),
`and publications. The CTC have been used widely for collecting treatment-related
`adverse event data to facilitate the evaluation of new cancer therapies, treatment
`modalities, and supportive measures. The original version of the CTC had 49 adverse
`event terms grouped in 18 categories, each with criteria for grading the severity of the
`adverse event. In the intervening years, in an effort to report additional adverse events
`seen in their studies, many groups independently added supplemental adverse event
`criteria to describe adverse events that were not originally included. Consequently,
`criteria adopted by various groups differed. To improve completeness, accuracy, and
`precision of the CTC, and to standardize reporting across groups and therapeutic
`modalities, a Common Toxicity Criteria Review Committee was assembled to revise and
`expand the CTC to meet current needs.
`1.1
`Purpose of this Manual
`
`This manual has been developed to assist users in making the transition from the original
`CTC to the revised and expanded Cancer Therapy Evaluation Program, Common
`Toxicity Criteria, Version 2.0 (CTC, v2.0) and to introduce investigators who have never
`used the CTC to this grading system.
`1.2 Making the Entire CTC Available to those Responsible for Grading
`Adverse Events
`
`To ensure accuracy, the entire CTC, v2.0 should be readily available to those grading
`adverse events at each site where patients are evaluated. NCI only requires grading of
`those adverse events that occur (unless a protocol mandates grading of specific terms,
`even when they do not occur).
`1.3
`Defining Adverse Event
`• Toxicity – Toxicity is NOT clearly defined by regulatory organizations. The term
`toxicity is generally used for an adverse event that is possibly, probably, or
`definitely related to the agent or treatment.
`Note: The Cancer Therapy Evaluation Program CTC, v2.0 continues to use the
`term “toxicity” for historical reasons, but recommends that the term “adverse
`event” with its attributes be used instead whenever possible.
`• Adverse Event – Any unfavorable or unintended symptom, sign, or disease
`(including an abnormal laboratory finding), temporally associated with the use of
`a medical treatment or procedure that may or may NOT be considered related to
`the medical treatment or procedure.
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`1.4
`
`Specificity of the CTC
`
`The CTC, v2.0 and its associated grading criteria are very specific. Although more
`individual adverse events are included in the new version, the number of events a patient
`experiences will not change. In the revision process, care was taken to ensure that,
`wherever possible, each adverse event represented a single clearly definable clinical
`entity. In most instances, the CTC, v2.0 will provide an adverse event term and grade
`that more precisely describes the adverse event. The compilation of adverse events used
`to describe an incident will provide more complete characterization of the events that
`occur; they do not necessarily indicate more toxic agents. The goal of the CTC, v2.0 is to
`facilitate a description of the adverse events that do occur. The CTC, v2.0 includes “Also
`Consider” notes associated with adverse events to direct the user toward other adverse
`events that require grading if they also occurred.
`2. ORGANIZATION OF THE CTC
`The CTC, v2.0 includes 24 categories of adverse events with more than 200 individual
`adverse events. In addition, there are six appendices fully described in Section 2.6.
`2.1 Adverse Event Categories in the Revised CTC
`
`The primary organization of the CTC, v2.0 is based on pathophysiological (e.g.,
`Allergy/Immunology) and anatomical (e.g., Dermatology/Skin) categories to facilitate
`location of related adverse events. The following is a list of categories of adverse events
`in the CTC, v2.0; new categories or categories with expanded titles are identified by bold
`type.
`
`• INFECTION OR FEBRILE NEUTROPENIA
`• LYMPHATICS
`• METABOLIC/LABORATORY
`• MUSCULOSKELETAL
`
`Categories in the CTC, v2.0
`• ALLERGY/IMMUNOLOGY
`• AUDITORY/HEARING
`• BLOOD/BONE MARROW
`• CARDIOVASCULAR
`(ARRHYTHMIA)
`• NEUROLOGY
`• CARDIOVASCULAR (GENERAL)
`• COAGULATION
`• OCULAR/VISUAL
`• CONSTITUTIONAL SYMPTOMS
`• PAIN
`• PULMONARY
`• DERMATOLOGY/SKIN
`• RENAL/GENITOURINARY
`• ENDOCRINE
`• GASTROINTESTINAL
`• SECONDARY MALIGNANCIES
`• HEMORRHAGE
`• SEXUAL/REPRODUCTIVE FUNCTION
`• HEPATIC
`• SYNDROMES
`Within each of these categories, specific adverse events are listed alphabetically and
`graded.
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`2.2 Adverse Event Listings
`
`In revising the CTC, attention was directed to adverse events that occur with varying
`cancer therapies and patient populations. The CTC, v2.0 classifies adverse events that
`occur with investigational treatments including chemotherapy, biological therapy,
`radiation therapy, and surgery. For selected adverse events, different grading criteria are
`provided together for different patient populations. The adverse event name is the same;
`only the criteria for grading are changed. All special criteria are identified by shaded text.
`For pediatrics and radiation therapy, these pertinent criteria should be used routinely.
`• For the pediatric population special adverse events and grading criteria have
`been added to account for such child-specific problems as developmental deficits
`or adjusted laboratory values. Pediatric adverse events or notes referring to
`pediatric adverse events are identified by italic type.
`• Adverse events and grading criteria specially developed by RTOG for radiation
`therapy are included.
`• Special optional criteria for bone marrow transplant have been added to describe
`and grade some adverse events. Also optional is the BMT-related
`Complex/Multicomponent Events Appendix included to facilitate the evaluation
`of events according to published criteria.
`The following adverse events must be specified in the protocol if these alternative
`criteria proposed by leukemia and bone marrow transplant experts are to be used.
`• Leukemia – criteria requiring calculations for grading changes in Hemoglobin,
`Platelets, Neutrophils, and Fibrinogen.
`• Bone marrow transplant – Leukocytes, Platelets, Transfusion: platelets,
`Transfusion: pRBCs, Weight gain VOD, Bilirubin-GVHD, and
`Stomatitis/pharyngitis.
`• Appendix for BMT-related Complex/Multicomponent Events.
`When selecting which criterion to use, choose the one most consistent with the patient
`population or treatment modality.
`2.3 Grades of Adverse Events
`
`For each adverse event, grades are assigned and defined using a scale from 0 to 5 with 0
`representing no adverse event within normal limits and 5 representing death related to an
`adverse event. Specific criteria for each grade are included for each adverse event.
`0 = No adverse event or within normal limits
`1 = Mild adverse event
`2 = Moderate adverse event
`3 = Severe and undesirable adverse event
`4 = Life-threatening or disabling adverse event
`5 = Death related to adverse event
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`Grading is based on specific clinical criteria that usually require evaluation by the
`clinician.
`
`Example: CARDIOVASCULAR Category
`An acute myocardial infarction would be graded within the CARDIOVASCULAR
`(GENERAL) category using the grading for Cardiac-ischemia/infarction.
`Grade
`
`Adverse Event
`Cardiac-ischemia/infarction
`
`1
`non-specific T – wave
`flattening or changes
`
`2
`asymptomatic, ST –
`and T – wave changes
`suggesting ischemia
`Acute myocardial infarction would be graded as Cardiac-ischemia/infarction, Grade 4.
`2.4 Adverse Events Not Included in the CTC, v2.0
`
`3
`angina without
`evidence of infarction
`
`4
`acute myocardial
`infarction
`
`Adverse events not included in the CTC, v2.0 should be reported and graded under the
`“Other” adverse event within the appropriate category and graded as mild (Grade 1),
`moderate (Grade 2), severe (Grade 3), life-threatening or disabling (Grade 4), or fatal
`(Grade 5) using the general definitions provided. New adverse events may be submitted
`to the NCI CTEP Help Desk where the CTC Change Management Committee will
`compile them for annual evaluation. A subcommittee for the CTC Revision Group will
`assess new adverse event terms for inclusion in future updates.
`2.5 Where to Find Adverse Events from the 1982 Version of the CTC
`
`Many of the adverse events included in the 1982 version of the CTC have been retained
`in the current version. In many cases, the names of the adverse events have been
`retained, but the grading criteria have been refined. In other cases, original adverse
`events have been split into two or more different adverse events. Several examples of
`these are displayed below:
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`Transaminase
`
`Weight gain/loss
`
`CTC 1982 Version CTC, v2.0
`Pulmonary
`Adult Respiratory Distress Syndrome (ARDS)
`Carbon monoxide diffusion capacity (DLCO)
`Cough
`Dyspnea
`FEV1
`Hypoxia
`Pneumonitis/infiltrates
`Pneumothorax
`Pulmonary fibrosis
`SGOT (AST)
`SGPT (ALT)
`Weight gain
`Weight loss
`Weight gain - Veno-Occlusive Disease (VOD)
`2.6 Highlights of Important Changes
`Some specific changes in the CTC, v2.0 include:
`• Some adverse events now contain “Also Consider” notes that ask the clinician to
`consider other adverse events that frequently occur in association. If any are
`present, they should also be graded.
`In the BLOOD/BONE MARROW category, criteria for the Platelets Grade 4 has
`changed from <25,000/mm2 to <10,000/mm2.
`• Cardiovascular adverse events have been divided into two separate categories,
`CARDIOVASCULAR (ARRHYTHMIA) and CARDIOVASCULAR
`(GENERAL). Many of the new adverse event terms are very specific and require
`diagnostic procedures and evaluation by a clinician, e.g., specific arrhythmias are
`identified from ECG tracings. Only when symptoms suggesting an irregular
`heartbeat are reported by a patient in the absence of confirmatory ECG diagnostic
`of a specific arrhythmia, should Palpitations be graded.
`In the CONSTITUTIONAL SYMPTOMS category, Weight gain and Weight loss
`are included as separate adverse events. When there is an obvious reason for the
`change in weight such as ascites, edema, pleural effusion, dehydration, vomiting,
`or diarrhea, also grade the condition causing the weight gain or loss unless it is
`definitely tumor-related. If no cause is apparent, grade only Weight gain or
`Weight loss. An additional adverse event, Weight gain-VOD has been added for
`use in describing weight changes that occur in Veno-Occlusive Disease (VOD) in
`bone marrow transplant patients.
`• There are four important notes at the beginning of the HEMORRHAGE category
`to provide overall guidance on grading adverse events in this category. New
`
`•
`
`•
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`adverse event terms have been added to differentiate between
`Hemorrhage/bleeding with Grade 3 or 4 thrombocytopenia and
`Hemorrhage/bleeding without Grade 3 or 4 thrombocytopenia.
`• Adverse Events in the INFECTION/FEBRILE NEUTROPENIA category are
`categorized as to whether they occurred with or without neutropenia. The adverse
`event Infection with unknown ANC is available for use in the rare instance when
`an infection occurs with an unknown neutrophil count. Catheter-related infection
`is a new, additional adverse event.
`• The adverse event terms in the NEUROLOGY category have been extensively
`revised to provide more specific adverse event descriptions. A number of grading
`criteria in the original CTC have been split into separate adverse events and
`graded.
`• The PAIN category includes a variety of sites of pain. The intent of this category
`is to describe pain that may result from (or be exacerbated by) treatment, not pain
`due to underlying disease alone. One adverse event, Tumor pain is reserved for
`pain localized to tumor that begins or is exacerbated in relationship to therapy. It
`is not to be used when there is no change from baseline or when worsening is
`clearly due to tumor progression.
`2.7 Appendices to the CTC
`Appendices I to VI are described below:
`• Appendix I: Adverse Event Module for the rare situation when a sponsor or
`principal investigator requires more detail regarding specific
`adverse events. This module is required only when mandated by
`the protocol, generally when a new or previously undescribed
`adverse event is identified.
`• Appendix II: Infection Module for detailed information regarding infections in
`the rare situations where additional detail is required. This module
`is required only when mandated by the protocol.
`• Appendix III:Performance Status Scales/Scores.
`• Appendix IV:RTOG/EORTC Late Radiation Morbidity Scoring includes
`adverse events that occur more than 90 days after initiation of
`radiation therapy. These criteria were previously developed by
`RT0G and EORTC and have not been revised.
`• Appendix V: BMT-Specific Adverse Events for a summary of BMT-Specific
`Adverse Events that may be used if specified by the protocol.
`These differ from the standard CTC and may be more relevant to
`the transplant setting. They are included in the CTC document and
`listed separately in Appendix V for the convenience of
`investigators writing transplant protocols.
`• Appendix VI:BMT Complex/Multicomponent Events.
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`3. HOW TO GRADE ADVERSE EVENTS
`3.1 What Not to Grade
`• Disease progression or signs and symptoms definitely related to disease should
`not be graded.
`Treatment delivery system malfunctions or sequelae related only to the treatment delivery
`system, such as a broken needle requiring excision, should not be graded as adverse
`events.
`3.2 Attribution of Causality
`
`To ensure that treatment-related conditions are distinguished from disease-related
`conditions, attribution of causality is a critical though often difficult first step in grading
`adverse events. All symptoms, signs, or diseases (including abnormal laboratory
`findings), that might be associated with investigational agents or therapies must be
`captured and graded. For each event, the attending physician or clinician in conjunction
`with the research nurse who examined and evaluated the patient, should assign the
`attribution. This important task must not be performed by data managers who are
`removed from the clinical assessment of the patient.
`Attribution should be determined using the following criteria:
`ATTRIBUTION OF ADVERSE EVENTS
`Code Descriptor
`5
`Definite
`
`Definition
`The adverse event is clearly related to the investigational
`agent(s)
`The adverse event is likely related to the investigational agent(s)
`The adverse event may be related to the investigational agent(s)
`The adverse event is doubtfully related to the investigational
`agent(s)
`The adverse event is clearly not related to the investigational
`agent(s)
`Investigators must document and grade adverse event data if there is any probable,
`possible or definite relationship to the agent. Adverse events that are definitely related to
`disease should not be graded. If an adverse event is caused by a combination of
`treatment and disease, the adverse event should be graded as it is observed with no
`adjustment. Early in the development of an agent, when little is known of an agent’s
`safety profile, it is especially important to maintain a high level of suspicion and report
`adverse events that may be agent-related adverse events. Careful reporting is needed to
`identify idiosyncratic or low frequency agent-related adverse events that may not yet
`have been identified.
`Note that requirements for expedited reporting for serious and unexpected events are
`specified in each protocol.
`
`4
`3
`2
`
`1
`
`Probable
`Possible
`Unlikely
`
`Unrelated
`
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`3.3 Grading at Baseline
`
`Investigators are encouraged to record baseline values as course 0, though NCI does not
`currently provide a mechanism for electronic capture of baseline data in the Clinical Data
`Update System (CDUS). Course 0 baseline pretreatment information will be considered
`for future updates of the CDUS. No modification in grading should be made to account
`for abnormalities noted at baseline. For example, if a patient enters a trial with an AST
`value twice the upper limit of normal (Grade 1) and at the end of cycle two of therapy the
`AST is 6 times the upper limit of normal, Grade 3 AST should be reported (in this case,
`course 0 or baseline AST would be Grade 1). Note that the availability of Course 0
`information allows subsequent analysis of AST abnormalities according to whether
`patients had preexisting hepatic abnormalities or not.
`3.4 Documenting Related Adverse Events
`
`In some cases an adverse event will be associated with the occurrence of one or more
`additional adverse events. These may or may not require grading, depending upon the
`specific case. In general, related adverse events must be graded when the related adverse
`event is clinically significant and provides relevant information to allow evaluators of the
`data to more fully characterize an adverse event. If several adverse events are actually
`due to one primary diagnosis, it is generally not necessary to include all of the
`components because they are expected. Several examples follow.
`
`•
`
`Example: GASTROINTESTINAL Category
`A patient has diarrhea with dehydration causing hypotension and requiring parenteral
`support.
`• The classification of Diarrhea as Grade 3 requires an increase of ≥ 7 stools per
`day, or be so severe that parenteral support is required for dehydration.
`If dehydration did occur, it should also be graded. The dehydration may be:
`Grade 2, requiring IV fluid replacement (brief);
`Grade 3, requiring IV fluid replacement (sustained); or
`Grade 4, hypotension requiring intensive care or
`hemodynamic collapse.
`If the resulting dehydration is Grade 4, then hypotension in the CARDIOVASCULAR
`(GENERAL) category also should be graded.
`Grade
`
`Adverse Event
`Diarrhea
`patients without colostomy:
`
`1
`increase of <4
`stools/day over pre-
`treatment
`
`2
`increase of 4-6
`stools/day, or nocturnal
`stools
`
`3
`increase of ≥7
`stools/day or
`incontinence; or need
`for parenteral support
`for dehydration
`
`4
`physiologic
`consequences requiring
`intensive care; or
`hemodynamic collapse
`
`!
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`Adverse Event
`Dehydration
`
`1
`dry mucous
`membranes and/or
`diminished skin turgor
`
`Grade
`
`2
`requiring IV fluid
`replacement (brief)
`
`3
`requiring IV fluid
`replacement
`(sustained)
`
`4
`physiologic
`consequences requiring
`intensive care;
`hemodynamic collapse
`
`Also consider Diarrhea, Vomiting, Stomatitis/pharyngitis (oral/pharyngeal mucositis), Hypotension.
`
`3
`requiring therapy and
`sustained medical
`attention, but resolves
`without persisting
`physiologic
`consequences
`
`4
`shock (associated with
`acidemia and impairing
`vital organ function
`due to tissue
`hypoperfusion)
`
`!G
`
`rade
`
`2
`requiring brief fluid
`replacement or other
`therapy but not
`hospitalization; no
`physiologic
`consequences
`
`1
`changes, but not
`requiring therapy
`(including transient
`orthostatic
`hypotension)
`
`Adverse Event
`Hypotension
`
`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.
`
`Example: HEMORRHAGE Category
`A patient with 20,000 platelets has a hemorrhage of the lower GI tract requiring both
`platelet transfusion and packed red blood cell transfusion. Her hemoglobin is 7.0 g/dL.
`The adverse event Hemorrhage/bleeding with Grade 3 or 4 thrombocytopenia requires
`that the site or type of bleeding be reported as well as Platelets, Hemoglobin, and, if
`given, Platelet transfusion, and/or pRBC transfusion.
`Grade
`
`1
`mild without
`transfusion
`
`2
`
`4
`Adverse Event
`catastrophic bleeding,
`Hemorrhage/bleeding with
`requiring major non-
`grade 3 or 4
`elective intervention
`thrombocytopenia
`Also consider Platelets, Hemoglobin, Transfusion: platelets, Transfusion: pRBCs, site or type of bleeding. If the site is not listed, grade
`as Hemorrhage-Other (Specify site, ___________).
`Note: This adverse event must be graded for any bleeding with grade 3 or 4 thrombocytopenia.
`
`3
`requiring transfusion
`
`3
`requiring transfusion
`
`4
`catastrophic bleeding,
`requiring major non-
`elective intervention
`
`!G
`
`rade
`
`!
`
`Adverse Event
`Melena/GI bleeding
`
`1
`mild without
`transfusion
`
`2
`-
`
`13
`
`

`
`Common Toxicity Criteria Manual
`
`3
`≥10.0 - <50.0 x 109 /L
`≥10,000 -
`<50,000/mm3
`≥10.0 - <20.0 x 109 /L
`≥10,000 -
`<20,000/mm3
`50 - <75% decrease
`from baseline
`
`4
`<10.0 x 109 /L
`<10,000/mm3
`
`<10.0 x 109 /L
`<10,000/mm3
`
`≥75% decrease from
`baseline
`
`3
`6.5 - <8.0 g/dL
`65 - <80 g/L
`4.0 - <4.9 mmol/L
`50 - <75% decrea