Reporting Results of Cancer Treatment
`
`A. 8. MILLER, MB, FRCP(C), B. HOOGSTRATEN, MD, M. STAQUET, MD, AND A. WINKLER, MD’
`
`On the initiative of the World Health Organization, two meetings on the Standardization of Reporting
`Results of Cancer Treatment have been held with representatives and members of several organizations.
`Recommendations have been developed for standardized approaches to the recording of baseline data
`relating to the patient, the tumor, laboratory and radiologic data, the reporting of treatment, grading
`of acute and subacute toxicity, reporting of response, recurrence and disease-free interval, and re-
`porting results of therapy. These recommendations, already endorsed by a number of organizations,
`are proposed for international acceptance and use to make it possible for investigators to compare
`validly their results with those of others.
`Cancer 47207-214. 1981.
`
`A continual investigation and evaluation of treat-
`
`DVANCES
`
`IN CANCER THERAPY are made by
`
`ment results and their incorporation in the practice of
`oncology. This requires comparisons between results
`and necessitates the availability of appropriate data
`in a suitable form. Thus, standardization of assessment
`and of reporting of results is an important step that
`aims at increasing the amount of usable therapeutic
`information at the disposal of the physician. It has,
`therefore, become necessary to develop a “common
`language” to describe the results of cancer treatment
`and to agree upon internationally acceptable general
`principles for reporting and assessing data.
`
`* Writing Committee Representing the Participants at the Meetings
`on Standardization of Reporting of Results of Cancer Treatment,
`Turin 1977 and Brussels 1979.
`Address for reprints: A. B. Miller, MB, Director, NCIC
`Epidemiology Unit, Faculty of Medicine, McMurrich Building,
`University of Toronto, 12 Queen’s Park Crescent West, Toronto,
`Ontario M5S 1A8.
`The participants were the following: P. Alberto, MD, Swiss
`Group for Clinical Cancer Research, Geneva, Switzerland; E.
`Anglesio, MD, Registro dei Tumori per il Piemonte e la Valle
`d’Aosta. Turin, Italy (Chairman Turin meeting); M. Bayssas, MD,
`Institut de Cancerologie et d’lmmunogenetique, Villejuif, France;
`N. M. Bleehen, MD, Cambridge University School of Clinical
`Medicine, Cambridge, UK (Representing British Medical Re-
`search Council); Z. Brzezinski, MD, WHO Regional Office for
`Europe, Copenhagen, Denmark; K. Calman, MD, University of
`Glasgow, Glasgow, UK; S. K. Carter, MD, Northern California
`Cancer Program, Palo Alto, California; N. Cascinelli, MD, In-
`stitute Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy;
`V. Cerny, MD, Institute of Clinical Oncology, Bratislava, Czech-
`oslovakia (Representing Council for Mutual Economic Aid); H.
`Davis, MD, Wisconsin Clinical Cancer Center. Madison, Wis-
`consin, (Representing National Cancer Institute, USA); S. Eckhardt,
`MD, Chairman of Trial Center for Council for Mutual Economic
`Aid. Budapest. Hungary; A. M. Garin, MD, Cancer Research Center
`of the Academy of Medical Sciences, Moscow, USSR (Representing
`Council for Mutual Economic Aid); M. Hakama, ScD, Finnish
`Cancer Registry, Helsinki, Finland; J. L. Hayward, MB, Guy’s
`Hospital. London (Vice-chairman, Turin meeting); H. Hansluwka.
`
`On the initiative of the World Health Organization,
`two meetings on the Standardization of Reporting
`Results of Cancer Treatment have been held in Turin,
`1977 and in Brussels, 1979 with representatives of the
`European Organization for Research on Treatment of
`Cancer, the National Cancer Institute USA, the Inter-
`national Union Against Cancer, the Council for Mutual
`Economic Aid (COMECON), as well as members of
`several other organizations (ECOG, MRC, SAKC,
`SWOG, VA). This report is a summary of the con-
`clusions and recommendations resulting from these
`combined efforts. A WHO technical report has been
`published in handbook form by the World Health
`
`MD, WHO HQ, Geneva, Switzerland: G. A. Higgins, Jr., MD, Veterans
`Administration Hospital. Washington, D.C.; B. Hoogstraten, MD,
`University of Kansas Medical Center, Kansas City, Kansas,
`(Rapporteur. Brussels Meeting); H. Ichikawa, MD, National
`Cancer Center, Tokyo, Japan; A. C. C. Junqueira, MD, A.C.
`Camargo Hospital, Sao Paulo, Brazil (Representing International
`Union Against Cancer); K. Karrer, MD, Institut fur Krebsforschung
`der Universitat Wien, Vienna, Austria; Y. Kenis. MD, Institut Jules
`Bordet. Brussels, Belgium; D. Kisner, MD, Division of Cancer
`Treatment, National Cancer Institute, Bethesda, Maryland; Dr.
`B. Luboinski, MD, Institut Gustave-Roussy, Villejuif, France;
`K. Magnus, PhD, The Cancer Registry of Norway, Oslo, Norway;
`G. Mathe, MD. Institut de Cancerologie et d’Immunogenetique,
`Villejuif, France; A. B. Miller, MB. University of Toronto, Canada
`(Rupportrur Turin Meeting and Chairman Brussels Meeting);
`H. Mouriesse, lnstitut Gustave Roussy, Villejuif. France: V. Ngu.
`MD, University of Yaounde, United Republic of Cameroon;
`0. Selawry. MD, University of Miami, Miami. Florida; A. 0. Sobo,
`MD, John F. Kennedy Medical Center, Monrovia, Liberia; M.
`Staquet, MD, Institut Jules Bordet, Brussels, Belgium (Vice-
`Chairman Brussels Meeting): H. Tagnon, MD, lnstitut Jules
`Bordet, Brussels, Belgium; 0. Takatani. MD, National Defense
`Medical College. Saitama-ken, Japan; B. Terracini. MD, Universita
`di Torino, Turin, Italy; N. Trapeznikov. MD, Cancer Research
`Center of the Academy of Medical Sciences, Moscow, USSR;
`G. P. Warwick, MD, International Union Against Cancer, Geneva,
`Switzerland; A. Winkler, MD, Cancer Unit, WHO, Geneva.
`Accepted for publication January 21, 1980.
`
`0008-543X/81/0101/0207 $0.90 0 American Cancer Society
`207
`
`1 of 8
`
`Celltrion, Inc., Exhibit 1029
`
`

`

`208
`
`CANCER January 1 198 1
`
`VOl. 47
`
`Organization.s The guidelines given here are meant to
`be minimal requirements, leaving the investigator free
`to add any variable he deems necessary.
`
`Baseline Data
`Minimum sets of patient and tumor characteristics
`are necessary for identification of the patient popula-
`tion under therapy. This minimum allows for a more
`complete evaluation of the reported data and results.
`Useful for this purpose are some of the recommenda-
`tions in the WHO Handbook for Standardized Cancer
`Registries.'
`
`Minimum Dato about the Patient
`The minimum data should include name of the
`patient, address, hospital number or other identifica-
`tion number, sex, year of birth, birth place, height and
`weight, relevant medical history, all prior antitumor
`therapy, and performance status.
`Performance status classification can be according
`to the Karnofsky scale (10 points)4 or preferably using
`a 5-grade scale9: grade 0-able
`to carry out all normal
`activity without restriction; grade 1 -restricted
`in
`physically strenuous activity but ambulatory and able
`to do light work; grade 2-ambulatory
`and capable
`of all self-care but unable to carry out any work.
`Up and about more than 50% of waking hours; grade
`3-capable
`of only limited self-care, confined to bed
`or chair more than 50% of waking hours; grade 4-
`completely disabled. Cannot carry on any self-care.
`Totally confined to bed or chair.
`It is often helpful to obtain additional data such as
`nutritional status, specific habits, and socioeconomic
`status. These and similar factors, which may influence
`the behavior of the neoplasm or the antitumor
`therapy, should be specified when indicated.
`
`Data about the Tumor
`The minimum data set desirable follows.
`the primary: ICD-O is recommended for
`Site of
`topography coding.3
`Measurability of the disease: Mention should be
`made whether the tumor or lesions are measurable:
`measurable, bidimensional; measurable, unidimen-
`sional or non-measurable but evaluable.
`Measurable, bidimensional: Malignant disease meas-
`urable (metric system) in two dimensions by ruler or
`caliper with surface area determined by multiplying the
`longest diameter by the greatest perpendicular di-
`ameter (i.e., metastatic pulmonary nodules, lymph
`nodes, and subcutaneous masses). Institutions per-
`
`forming life-size liver scans may use clearly defined
`biopsy-proved malignant hepatic nodules measuring
`greater than 5 cm in diameter as measurable disease.
`Measurable, unidimensional: Malignant disease
`measurable (metric system) in one dimension by ruler
`or calipers (i.e., mediastinal adenopathy, malignant
`hepatomegaly, or abdominal masses).
`Mediastinal and hilar involvement may be measured,
`if a preinvolvement chest x-ray is available, by sub-
`tracting the normal mediastinal or hilar width on the
`preinvolvement x-ray from the on-study width con-
`taining malignant disease.
`Malignant hepatomegaly may be measured if the liver
`descends 5 cm below the costal margin by adding the
`measurements below the costal margins in the mid-
`clavicular line and the tip of the xiphoid. Measure-
`ments below the costal margins should be made in the
`midclavicular lines or at other specifically defined
`points during quiet respiration.
`Nonmeasuruble, evaluable: Malignant disease evi-
`dent on clinical (physical or radiographic) examination,
`but not measurable by ruler or calipers (i.e., pelvic
`and abdominal masses, lymphangitic or confluent
`multinodular lung metastases, skin metastases).
`When applicable, photographs should be taken
`before and during therapy to document response
`(i.e., skin and subcutaneous metastases, inflammatory
`breast cancer, intraoral lesions, or recurrent rectal
`cancer).
`Chemical values and biologic markers should be
`measured during therapy but are not used to evaluate
`response, unless specifically stipulated in individual
`protocols.
`Histopathology, tumor type, grude
`ICD-0 morphology codes should be
`the diseasc: Clinical staging
`Anatomical extent of
`should be recorded before the start of therapy. The
`UICC TNM system should be used whenever appli-
`cable.6 Where surgery has been used to complete the
`staging, the extent of the disease, what was examined
`and what was found, and
`the resulting surgico-
`pathologic stage should also be recorded.
`Laboratory ond radiologic data: It is suggested that
`the following be included: complete blood count, renal
`and liver function tests, pertinent radiologic assess-
`ment and tumor markers, if any.
`
`and stage: The
`
`~
`
`Reporting of Treatment
`Since the treatment methods should be reproducible,
`it is necessary to report sufficient information to inter-
`pret and evaluate the therapy used. It is important to
`indicate whether the specific therapy, be it a single
`
`2 of 8
`
`Celltrion, Inc., Exhibit 1029
`
`

`

`No. 1
`
`RESULTS OF CANCER TREATMENT
`* Miller et al.
`
`209
`
`mode or a combined modality, is used to induce an
`antitumour effect or to maintain a condition.
`In this report, the term “adjuvant therapy” is not
`used. What can be considered as adjuvant to primary
`therapy today may become primary tomorrow. It is
`therefore recommended that the term “combined
`modality therapy” be used when more than one form of
`treatment is used.
`
`S 11 rg e fi
`Precise description of the surgical procedures should
`be given, preferably in the following categories.
`I . Local excision of the tumor without excision of
`regional lymph nodes.
`2 . Local excision of the tumor with excision of the
`regional lymph nodes.
`3. Excision of the tumor with the involved organ
`without excision of the regional lymph nodes.
`4. Excision of the tumor with the involved organ
`with excision of the regional lymph nodes.
`5 . Excision of the tumor extended to adjacent
`organs. This can include removal of the involved organ
`where applicable.
`6. Partial excision of the tumor (reduction, de-
`bulking, or other).
`7. Excision of the metastatic lesions.
`8. Reconstructive surgery.
`9. Surgery for alleviation of symptoms only.
`10. Other surgery. i . r . . exploratory, second look.
`Whenever relevant, it is recommended that the
`surgeon states at the end of the operation whether the
`procedure is potentially curative or not. Major com-
`plications following surgery must be reported.
`
`Rrrtiiotht>mpy
`The following minimum specifications and descrip-
`tions are recommended: treatment plan; indications
`of whether the intent was curative or palliative; and
`the methodology, including the following.
`1. Source of radiation (e.g., isotope, treatment
`machine).
`2. Type of radiation (e.g., photon, neutron).
`3 . Energy of radiation.
`4. Method of application (e.g., external beam,
`interstitial).
`5. Sites treated including field sizes.
`6. Dosage-time relationship, specifying: total dose,
`individual doses, dose rate. fractionation scheme,
`and overall time.
`When treatment is not completed, the reason(s) for
`this should be stated. Radiosensitizers or protectors
`should be described when used.
`
`Chetnotherapy including Hormonal Therapy
`Precise description should be given of treatment
`plan and drugs.
`Description of drug administration should include
`drug name (use of nonproprietary name is recom-
`mended); routes and duration of administration: dos-
`ages (specify per kg of body weight or body surface in
`square meters and amount, e.g., mg, 8); schedule and
`duration. Specify whether the drugs used are given
`singly, concurrently, or in sequence.
`Give the proportion of planned doses actually
`administered if possible, and explain the reasons for
`dosage modifications or delays in drug administration.
`
`Itnrn i4n ot he rapy
`Precise description should be given of agents or
`materials used; sources and strains; routes and
`duration of administration; dosage; and frequency of
`administration.
`
`Combined Modality Therupy
`Each of the modalities should be described in-
`dividually. The time relationship of the different forms
`of therapy should be clearly specified, whether given
`concurrently, sequentially, during primary therapy,
`maintenance, or other.
`
`Reporting of Toxicity
`
`The management of malignancies frequently re-
`quires the use of treatment modalities that are as-
`sociated with significant toxic effects. The acceptability
`of specific therapy can be assessed by comparing its
`benefits with its potential cost in terms of toxicity. For
`this reason, the documentation of toxicity is a crucial
`part of reporting treatment results. For purposes of
`classification, toxicities are best divided into acute
`plus subacute and chronic or late, rather than into
`specific treatment modalities.
`
`Acute and Subacute Toxicity
`Grading of acute and subacute toxicity has several
`important advantages: it permits comparison of toxicity
`between treatment programs, it permits computerized
`storage and analysis of toxicity data. and it allows
`uniform treatment modification within the therapeutic
`programs.
`The attachment of clinical significance to a grade
`should be avoided. e.g., life threatening. A five grade
`system is recommended for general use, grades 0
`
`3 of 8
`
`Celltrion, Inc., Exhibit 1029
`
`

`

`2 10
`
`CANCER January I 1981
`
`Vol. 41
`
`TABLE 1 .
`
`Recommendations for Grading of Acute and Subacute Toxicity
`
`Grade 0
`
`Grade 1
`
`311.0
`
`24.0
`22.0
`2 100
`none
`
`9.5- 10.9
`
`3.0-3.9
`1.5-1.9
`75-99
`petechiae
`
`Grade 2
`
`8.0-9.4
`2.0-2.9
`
`Grade 3
`
`6.5-7.9
`
`1.0-1.9
`
`1.0-1.4
`50-74
`mild blood loss
`
`0.5-0.9
`25-49
`gross blood loss
`
`~ 1 . 2 5 x N*
`~ 1 . 2 5 x N
`~ 1 . 2 5 x N
`none
`
`1.26-2.5 x N
`1.26-2.5 x N
`1.26-2.5 x N
`soreness/erythema
`
`none
`
`none
`
`nausea
`
`transient <2 days
`
`~ 1 . 2 5 x N
`~ 1 . 2 5 x N
`none
`
`1.26-2.5 x N
`1.26-2.5 x N
`I+, ~ 0 . 3 dl00 ml
`
`microscopic
`
`2.6-5 x N
`2.6-5 x N
`2.6-5 x N
`erythema, ulcers,
`can eat solids
`transient vomiting
`
`tolerable but
`>2 days
`
`2.6-5 x N
`2.6-5 x N
`2-3+, 0.3-1.0
`g/100 ml
`gross
`
`5.1-10 x N
`5.1-10 x N
`5.1-10 x N
`ulcers, requires
`liquid diet only
`vomiting requiring
`therapy
`intolerable requiring
`therapy
`
`5-10 x N
`5-10 x N
`4 + , >1.0 g/100 ml
`gross + clots
`
`mild symptoms
`
`exertional dyspnea
`
`dyspnea at rest
`
`fever <38 C
`
`fever 38 C-40 C
`
`fever >40 C
`
`none
`
`none
`
`none
`
`Hematologic (Adults)
`Hemoglobin (g/lOO ml)
`Leukocytes 1000kmm
`Granulocytes lOOOicmm
`Platelets IOOOicrnm
`Hemorrhage
`
`Gastrointestinal
`Bilirubin
`SGOTlSGPT
`Alkaline phosphatase
`Oral
`
`Nauseaivomiting
`
`Diarrhea
`
`Renal, bladder
`BUN or blood urea
`Creatinine
`Proteinuria
`
`Hematuria
`
`Pulmonary
`
`Fever-Drug
`
`Allergic
`
`none
`
`edema
`
`Cutaneous
`
`none
`
`erythema
`
`bronchospasm, no
`parenteral
`therapy needed
`dry desquamation,
`vesiculation,
`pruritus.
`
`bronchospasm,
`parenteral therapy
`required
`moist desquamation,
`ulceration
`
`Hair
`
`Infection (specify site)
`
`Cardiac
`Rhythm
`
`Function
`
`Pericarditis
`
`none
`
`none
`
`none
`
`none
`
`none
`
`minimal hair loss
`
`minor infection
`
`moderate, patchy
`alopecia
`moderate infection
`
`complete alopecia
`but reversible
`major infection
`
`sinus tachycardia
`> 110 at rest
`asymptomatic, but
`abnormal cardiac
`sign
`
`asymptomatic
`effusion
`
`unifocal PVC
`atrial arrythmia
`transient
`symptomatic
`dysfunction, no
`therapy required
`symptomatic, no
`tap required
`
`multifocal PVC
`
`symptomatic
`dysfunction
`responsive to
`therapy
`tamponade, tap
`required
`
`Grade 4
`
`<6.5
`
`<1.0
`~ 0 . 5
`<25
`debilitating blood
`loss
`
`>10 x N
`>I0 x N
`>10 x N
`alimentation not
`possible
`intractable vomiting
`
`hemorrhagic
`dehydration
`
`>I0 x N
`>I0 x N
`nephrotic syndrome
`
`obstructive
`uropathy
`complete bed rest
`required
`fever with
`hypotension
`
`anaphylaxis
`
`exfoliative
`dermatitis,
`necrosis requiring
`surgical inter-
`vention
`nonreversible
`alopecia
`major infection
`with hypotension
`
`ventricular
`tachycardia
`symptomatic
`dysfunction
`nonresponsive to
`therapy
`tamponade, surgery
`required
`
`4 of 8
`
`Celltrion, Inc., Exhibit 1029
`
`

`

`No. 1
`
`RESULTS OF CANCER TREATMENT . Miller et ul.
`
`21 1
`
`TABLE 1.
`
`(Confinued)
`
`Grade 0
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Neurotoxicity
`State of consciousness
`
`Peripheral
`
`alert
`
`none
`
`transient lethargy
`
`paresthesias
`and/or decreased
`tendon reflexes
`
`somnolence 4 0 %
`of waking hours
`severe paresthesias
`and/or mild
`weakness
`
`Constipationt
`
`none
`
`mild
`
`Pain$
`* N = upper limit of normal.
`t Constipation does not include constipation resulting from
`narcotics.
`
`none
`
`mild
`
`through 4 (Table 1). N o attempt has been made to be all
`inclusive and investigators will undoubtedly need to
`add some toxic manifestations.
`Several forms of cancer treatment can result in or
`contribute to death. Such deaths must be reported
`separately.
`
`Chronic und Late Toxicity
`Chronic and late toxicities are becoming more
`common as more effective treatments result in longer
`survival. The severity of these toxicities is less easily
`quantified than acute states. It is suggested that the
`following be reported: organ site or system affected:
`timing in relation to presumed causative therapy;
`nature of toxicity or disability (include second malig-
`nancy); magnitude of symptoms; impact on perform-
`ance status; therapy required; response to therapy.
`Patients should be evaluated annually for chronic
`and late toxicity.
`
`Reporting of Repsonse
`The guidelines proposed by the Breast Cancer Task
`Force in the USA', and those proposed for breast
`cancer by the UICC project2 have in large measure
`been the basis for the criteria of response recommended
`in this report.
`In the past, some groups and investigators have re-
`ported decreases of less than 50% in tumor size as
`responses. Often, it does not seem possible to deter-
`mine this with precision.s It is recommended that only
`complete or partial responses as defined in this report
`be used.
`While it is recognized that in some treatment trials
`shorter durations of response may be useful, in general
`
`somnolent > 50% of
`waking hours
`intolerable
`paresthesias
`and/or marked
`motor loss
`abdominal distention
`
`severe
`
`coma
`
`paralysis
`
`distention and
`vomiting
`intractable
`
`moderate
`
`moderate
`
`treatment-related pain is considered, not disease-
`$ Pain-only
`related pain. The use of narcotics may be helpful in grading pain,
`depending upon the tolerance level of the patient.
`
`four weeks should be used as the minimum duration
`of reported response.
`Objective response can be determined clinically,
`radiologically, biochemically, or by surgicopathologic
`restaging. The method of determining response should
`therefore always be specified.
`A 25% increase in one or more measurable lesions
`and appearance of a new lesions are recommended
`for defining progression of disease. This percentage
`should not necessarily be regarded as influencing the
`management of the patient.
`
`De3nitions of Objective Response
`Memuruble diseuse: Complete response (CR)-The
`disappearance of all known disease, determined by two
`observations not less than four weeks apart.
`Partial response (PR)-50%
`or more decrease in
`total tumor load of the lesions that have been measured
`to determine the effect of therapy by two observations
`not less than four weeks apart. Bidimensional: single
`lesion, greater than or equal to 50% decrease in tumor
`area (multiplication of longest diameter by the greatest
`lesions, a 50%
`perpendicular diameter); multiple
`decrease in the sum of the products of the perpen-
`dicular diameters of the multiple lesions. Unidimen-
`sional: greater than or equal to 50% decrease in linear
`tumor measurement. In addition there can be no ap-
`pearance of new lesions or progression of any lesion.
`No change (NC)-A
`50% decrease in total tumor
`size cannot be established nor has a 25% increase in
`the size of one or more measurable lesions been dem-
`onstrated.
`Progressive disease (PD)-25% or more increase in
`the size of one or more measurable lesions or the ap-
`pearance of new lesions.
`
`5 of 8
`
`Celltrion, Inc., Exhibit 1029
`
`

`

`212
`
`CANCER January 1 1981
`
`Vol. 47
`
`Non-measurable disease: Complete response (CR)-
`Complete disappearance of all known disease for at
`least four weeks.
`Partial response (PR)-Estimated decrease in tumor
`size of 50% or more for at least four weeks.
`No change (NC)-No
`significant change for at least
`four weeks. This includes stable disease, estimated
`decrease of less than 50%, and lesions with estimated
`increase of less than 25%.
`Progressive disease (PD)- Appearance of any new
`lesions not previously identified or estimated increase
`of 25% or more in existent lesions.
`
`Bone Metastases
`A separate set of response criteria are necessary
`for bone metastases.
`Complete response (CR)-Complete disappearance
`of all lesions on x-ray or scan for at least four
`weeks.
`Partial response (PR)-Partial decrease in size of
`lytic lesions, recalcification of lytic lesions, or de-
`creased density of blastic lesions for at least four
`weeks.
`No change (NC)-Because of the slow response of
`bone lesions, the designation of no change should not
`be applied until at least eight weeks have passed from
`start of therapy.
`in size of
`Progressive disease (PD)-Increase
`existent lesions or appearance of new lesions.
`Occurrence of bone compression or fracture and its
`healing should not be used as the sole indicator for
`evaluation of therapy.
`
`Determination of Overall Response in Solid Tumors
`Progression in any site indicates disease progression,
`despite objective responses in other sites.
`If the organ site complete and partial responses are
`greater than no change designations, the overall re-
`sponse will be partial.
`No change of evaluable disease does not detract from
`complete or partial responses in measurable sites, but
`the patients overall response will be partial.
`
`Duration of Response
`The period of complete response should last from the
`date the complete response was first recorded to the
`date progressive disease was first noted.
`In those who only achieve partial response, only the
`period of overall response should be recorded. The
`period of overall response lasts from the first day of
`
`treatment to the date of first observation of progressive
`disease.
`
`Subjective Response
`Definition of subjective response is difficult because
`there are so many factors that can influence it. De-
`spite this difficulty a response (e.g., weight gain or
`decrease in pain) can nevertheless be of great im-
`portance to the patient and may alert the physician to
`the possibility of an objective response.
`
`Reporting of Recurrence, Relapse, Disease-Free
`Interval, and Disease-Free Survival
`The terms “recurrence” or “relapse” are here used
`to indicate reappearance of disease after complete
`eradication and are preferentially applied for patients
`with early stage disease; whereas, the term “pro-
`gression” is usually reserved for patients with advanced
`disease.
`
`Date of First Recurrence
`This should be based on the onset of a sign. The date
`of first detection of a palpable lesion is acceptable only
`when the diagnosis of tumor involvement is subse-
`quently established. The diagnosis of recurrent disease
`by x-rays or scans should be dated from the first
`positive record, even if determined in retrospect.
`Disease specific markers and disease specific symp-
`toms may be used to back-date the time of recurrence.
`To define the time of recurrence as accurately as
`possible, one should specify the frequency of exami-
`nation and duration of follow-up. Time to recurrence
`or death should be measured from the first day of
`therapy.
`All dates should be recorded by those responsible
`for the care of the patient. Dates of first recurrence,
`relapse, metastasis and death should be confirmed by
`an independent reviewer whenever possible. Data
`based on suspicion alone should be reviewed to
`establish their accuracy. In addition, the case records
`of patients not reported as having recurrent disease
`should be scrutinized annually.
`
`Diagnosis
`One or more of the following must be positive for a
`diagnosis of recurrent disease to be acceptable:
`histology or cytology; progression of lesion originally
`considered suspicious only: response of lesion(s) to
`specific therapy; and autopsy.
`
`6 of 8
`
`Celltrion, Inc., Exhibit 1029
`
`

`

`No. 1
`
`RESULTS OF CANCER TREATMENT . Miller et a/.
`
`213
`
`Classification of Recurrence
`Lesions can be categorized broadly as locoregional
`or distant. A precise description of the sites of re-
`currence or metastasis should be given. Where radio-
`therapy has been employed, distinction should be
`made on whether disease has reappeared within the
`irradiated volume or not.
`
`Classification qf Cases
`At the time of analysis the following outcomes are
`possible for each case: alive without recurrence; alive
`with recurrence; alive, recurrence unknown; dead
`without recurrence; dead with recurrence; dead, re-
`currence unknown; lost without recurrence; lost with
`recurrence; and lost, recurrence unknown.
`
`Disease-Free Interval and Disease-Free Survival
`Disease-free interval or disease-free survival cover
`the period when there is no evidence of disease ac-
`tivity. The time elapsed between randomization or
`date of start of treatment and recurrence or death for
`each patient must be carefully recorded.
`
`Reporting Results of Therapy
`In the reporting of results, a division can be made into
`two broad categories.
`Frequency. The frequency of an event is usually the
`first factor computed to evaluate a treatment. It is the
`ratio between the number of events of interest over
`the total number of units at risk. It can represent the
`frequency of recurrences following primary therapy,
`the proportion of responders, the proportion of
`survivors, the frequency of treatment failure, etc.
`Duration. The duration of several parameters can be
`important. Examples are the duration of time to re-
`currence, duration of response, duration of survival.
`Consideration of both frequency and duration will
`improve the completeness of reports. For instance,
`following the treatment of a primary cancer, it is useful
`to learn not only the frequency of recurrence but
`also the time elapsed between treatment and re-
`currence as well as the survival. On the other hand,
`when advanced disease is being treated, it is necessary
`to determine the proportion of responders, the duration
`of the responses, as well as survival. Thus, the ap-
`propriate use of parameters can vary with the disease,
`the stage of that disease, and the treatment.
`Numeraton and denominators: The numerator is the
`number of patients in whom events occur during a
`given period of observation. The denominator is the
`
`total number of patients at risk during that same
`period. Many authors do not clearly define the
`numerator or denominator used to report their results.
`Often a denominator is used from which many patients
`in the original sample have been deleted. Reasons for
`deletion include loss to follow-up, early death, in-
`adequate data, failure to complete therapy due to
`toxicity, and refusal by the patient of further therapy.
`Such deletions can lead to a falsely high frequency or
`duration for a group.
`At least two of the following three denominators are
`recommended for reporting results: 1) Eligible and
`registered, or randomized. The reasons for ineligibility
`and the number of patients entered on study but
`subsequently found to be ineligible must be reported.
`2) Eligible, registered or randomized and treated . This
`includes all patients who were eligible, were registered,
`and were given therapy regardless of how little or how
`much therapy was given. 3) Eligible, registered or
`randomized and adequately treated.
`When other denominators are used, these should be
`clearly defined.
`Maturity ofduta: When a large proportion of patients
`has been followed for a short length of time, the re-
`porting of duration may be meaningless. Similarly,
`the frequency of recurrence may be low and as yet of
`limited importance. It is important, therefore, to ensure
`that data have matured long enough to provide
`precision in the reported results while the complete-
`ness of data should always be specified in reports. The
`length of observation period required will tend to vary
`with different tumors.
`Accuracy of dates: There are many forms of in-
`accuracy that can distort reported treatment results.
`A very important one is in the follow-up. If this is in-
`frequent or poor, patients may be considered lost to
`follow-up or even alive and healthy when in reality they
`may be dead. Before reporting results, therefore, every
`effort should be made to confirm the state of the
`patient’s health as well as the date on which an event
`occurs.
`The problem of cure: The definition of “cure” is
`difficult and by many considered impossible. One def-
`inition used is when a group of patients has a
`survival experience identical to that of the general
`population with the same distribution of demographic
`factors, i.e., when the relative survival ratio is one.
`Some prefer the term “recovered” for those patients
`for whom it is known that there is a low probability of
`subsequent death from the initial neoplasm. Another
`option is to regard the patient as cured when he or she
`has survived in a disease-free state long enough to
`
`7 of 8
`
`Celltrion, Inc., Exhibit 1029
`
`

`

`214
`
`CANCER January 1 1981
`
`VOl. 47
`
`enter a group with a known low probability of de-
`veloping a recurrence.
`
`Patient Population
`The patients to be considered in reporting results can
`be classified as follows: patients available for treat-
`ment; patients considered eligible and registered for a
`given therapy (criteria for eligibility and noneligibility
`should be specified); patients treated with a given
`therapy; patients adequately treated (the definition of
`adequate should be stated before therapy is started and
`not at the end of a study); and patients evaluable for
`efficacy of therapy.
`The term "evaluable" is often not defined. This is
`one of the reasons different results from the same
`therapy are given in separate reports. Therefore, it is
`necessary to describe clearly those patients not con-
`sidered evaluable. Patients evaluable for toxicity may
`not be evaluable for response.
`
`D i m tion
`The best method to summarize frequency and
`duration is the life table method because it takes into
`account the experience of all patients entered into a
`study. The method can be used to calculate survival,
`
`duration of response. disease-free interval and other
`sets of time intervals. Investigators not fully acquainted
`with the methods of calculation are encouraged to
`enlist the assistance of a medical statistical unit.
`
`REFERENCES
`1. Breast Cancer Task Force Treatment Committee, National
`Cancer