Definitions for Response and Progression in Ovarian [614474]

Definitions for Response and Progression in Ovarian
Cancer Clinical Trials Incorporating RECIST 1.1
and CA 125 Agreed by the Gynecological
Cancer Intergroup (GCIG)
Gordon John Sampson Rustin, MD, MSc, FRCP ,* Ignace V ergote, MD, PhD, Ț
Elizabeth Eisenhauer, MD, țEric Pujade-Lauraine, MD,§ Michael Quinn, MBBCh, MSc, MRCP ,||
Tate Thigpen, MD, ¶Andreas du Bois, MD, PhD,** Gunnar Kristensen, MD, PhD, ȚȚ
Anders Jakobsen, MD, țțSatoru Sagae, MD, PhD,§§ Kathryn Greven, MD,|||| Mahesh Parmar, MD, ¶¶
Michael Friedlander, MD, PhD,*** Andres Cervantes, MD, PhD, ȚȚȚand Jan V ermorken, MD, PhD țțț
Abstract: The Gynecological Cancer Intergroup (GCIG) has previously reached consen-
sus regarding the criteria that should be used in clinical trial protocols to define progression-
free survival after first-line therapy as well as the criteria to define response to treatment in
recurrent disease using the serum marker CA 125 and has specified the situations where
these criteria should be used. However, the publications did not include detailed definitions,
nor were they written to accommodate the new version of Response Evaluation Criteria In
Solid Tumors (RECIST) criteria (version 1.1) now available. Thus, we recommend that the
definitions described later in detail are incorporated into clinical trial protocols to maintain
consistency. The criteria for defining progression are now acceptable in clinical trials of
recurrent disease as they have since been validated (Pujade-Lauraine, personal communi-
cation, 2010). The GCIG requests that data from all clinical trials using these definitions are
made available to GCIG trial centers so that continual validation and improvement can be
accomplished. These definitions were developed from analyzing patients receiving cyto-
toxic chemotherapy and have not yet been validated in patients receiving molecular tar-
geting agents.
Key Words: CA 125, Ovarian cancer, Response, Progression, RECIST, Clinical trials
Received August 2, 2010.
Accepted for publication November 16, 2010.
(Int J Gynecol Cancer 2011;21: 419 Y423)
The Gynecological Cancer Intergroup has previously
reached consensus regarding the criteria that should be
used in clinical trial protocols to define progression-free
survival after first-line therapy1as well as the criteria to define
response to treatment in recurrent disease2using the serummarker CA 125, and have specified the situations where these
criteria should be used (Table 1). However, the publications
did not include detailed definitions nor were they written to
accommodate the new version of Response Evaluation Cri-
teria In Solid Tumors (RECIST) criteria (version 1.1) nowREVIEW ARTICLE
International Journal of Gynecological Cancer &Volume 21, Number 2, February 2011 419*Mount Vernon Hospital, Northwood, UK; †University Hospital
Leuven, Leuven, Belgium; ‡NCIC Clinical Trials Group, Kingston,
Ontario, Canada; §Hopital Hotel Dieu, Paris, France; ||Royal Women’ s
Hospital, Melbourne, Australia; ¶University of Mississippi School
of Medicine, Jackson, MS; **Dr Horst-Schmidt-Klinik, Wiesbaden,
Germany; ††Norwegian Radium Hospital, Oslo, Norway; ‡‡Vejle
Hospital, Vejle, Denmark; §§Sapporo Railway Hospital, Sapporo,Japan; ||||Wake Forest University Medical Center, Winston Salem,
NC; ¶¶MRC Clinical Trials Unit, London, UK; ***Prince of Wales
Cancer Centre, Randwick, NSW , Australia; †††Hospital Clı ´nico,
University of Valencia, Valencia, Spain; ‡‡‡Antwerp University Hos-
pital, Edegem, Belgium.
Address correspondence and reprint requests to Gordon John
Sampson Rustin, MD, MSc, FRCP , Department of
Medical Oncology, Mount Vernon Cancer Centre,
Northwood, Middlesex HA62RN, UK.
E-mail: grustin@nhs.net.Copyright *2011 by IGCS and ESGO
ISSN: 1048-891X
DOI: 10.1097/IGC.0b013e3182070f17
Copyright © 2011 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.

available.3Thus, we recommend that the definitions de-
scribed later in detail below are incorporated into clinical trial
protocols to maintain consistency. The criteria for defining
progression are now acceptable in clinical trials of recurrent
disease as they have since been validated (Pujade-Lauraine,
personal communication, 2010). The GCIG requests that data
from all clinical trials using these definitions are made
available to GCIG trial centers so that continual validation
and improvement can be accomplished. These definitions
were developed from analyzing patients receiving cytotoxic
chemotherapy and have not yet been validated in patients
receiving molecular targeting agents.
The GCIG recommends that for trials of relapsed ovar-
ian cancer, the following definition for response according
to CA 125 be used in addition to the updated RECIST 1.13
response criteria.
EVALUATION OF RESPONSE
ACCORDING TO CA 125
Definition of Response
A CA 125 response is defined as at least a 50% re-
duction in CA 125 levels from a pretreatment sample. The
response must be confirmed and maintained for at least
28 days. Patients can be evaluated according to CA 125 only
if they have a pretreatment sample that is at least twice the
upper limit of the reference range and within 2 weeks before
starting the treatment.
To calculate CA 125 responses accurately, the follow-
ing rules apply:
– Intervening samples and the 28-day confirmatory sample
must be less than or equal to (within an assay variability of
10%) the previous sample.
– Variations within the reference range of CA 125 levels will
not interfere with the response definition.
– For each patient, the same assay method must be used, and
the assay must be tested in a quality control scheme.
– Patients are not evaluable by CA 125 if they have received
mouse antibodies (unless the assay used has been shown
not to be influenced by human antimouse antibody4,5)o ri f
there has been medical and/or surgical interference with
their peritoneum or pleura during the previous 28 days (eg,
paracentesis). If assessing therapy that includes 2 treatment
modalities for relapse (eg, surgery and chemotherapy), any
CA 125 response results from both treatment modalities.
CA 125 cannot distinguish between the effects of the 2
treatments.The date when the CA 125 level is first reduced by 50%
is the date of the CA 125 response. To calculate response,
an intent-to-treat analysis should be used that includes all
patients with an initial CA 125 level of at least twice the
upper limit of the reference range as eligible and evaluable.
In addition, as a separate analysis, those patients who have a
CA 125 response and whose CA 125 level falls to within
the reference range can be classified as CA 125 complete
responders. In Tables 2 and 3 where CA 125 is stated as
normalised or normal, means within the reference range.
Patients who have a fall of CA 125 to within the reference
range but whose initial CA 125 was less than twice the upper
limit of the reference range have not had a CA 125 response
and cannot therefore be classified as a CA 125 complete
responder.
Evaluation of Response According to CA
125 in Patients Receiving First-Line Therapy
The CA 125 response definition was developed to
evaluate response to chemotherapy in patients with recurrent
ovarian cancer. If the patient has had combined modality
therapy as part of their first-line therapy (eg, surgery and
chemotherapy), CA125 response may be due to both or either
treatments, and it should be clearly stated that CA125 cannot
distinguish between the effects of the 2 treatments. It should
be also be noted that for a patient to be classified as a com-
plete responder according to RECIST, tumor marker levels
such as CA 125 must be within the reference range.
Evaluation of Response According to CA
125 in Patients Receiving Maintenance or
Consolidation Therapy
Patients whose CA 125 is greater than twice the upper
limit of the reference range when they start maintenance or
consolidation therapy can be evaluated using the GCIG CA
125 response definition. However, it should be noted that
there are no data to validate the implications of achieving CA
125 response in this setting with respect to progression-free
or overall survival. To prevent the prior therapy from inter-
fering with the response assessment, we recommend that 2
pretreatment samples no more than 8 weeks apart are required
if test treatment is given as part of maintenance or consoli-
dation therapy. For the test treatment to be evaluable ac-
cording to CA 125, there should be no more than a 10% fall
in CA 125 between the 2 pretreatment samples. The sample
closest in time to the test therapy should be considered the
pretreatment sample.TABLE 1. GCIG recommendations for CA 125 criteria for response and progression in various clinical situations
Use Recommended
by GCIGNot Standard and Needs
Further ValidationNot Recommended
by GCIG
First-line trials CA 125 progression Ca 125 response
Maintenance or consolidation trials CA 125 response and progression
Relapse trials CA 125 response and progressionRustin et al International Journal of Gynecological Cancer &Volume 21, Number 2, February 2011
420 *2011 IGCS and ESGO
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Evaluation of Best Overall Response in
Patients Without Initial Measurable Disease
and Evaluable by CA 125
CA 125 may be used to evaluate response in patients
without initial measurable disease either because no measurable
disease is evident on radiological imaging or because ap-
propriate imaging has not been performed as demonstrated in
Table 2.Evaluation of Best Overall Response in
Patients With Initial Measurable Disease
and Who are Also Evaluable by CA 125
A report that combines both CA 125 and RECIST 1.1
criteria is likely to include patients who are measurable by
one or both of the criteria and who may have events at dif-
ferent time points. It should be determined according to
Table 3. In patients who have measurable disease by bothTABLE 2. Evaluation of best overall response in patients without initial measurable disease and who are evaluable
by CA 125
CA 125 Nontarget Lesions *New Lesions Overall Serological ResponseBest Response for This
Category Also Requires
Response and Normalized CR No CR Confirmed and maintained
for at least 28 days Response Non-PD No PR
Normalized but no response Non-CR/Non-PD No SD
Non-PR/non-PD Non-PD No SD
PD Any Y es or No PD
Any PD † Ye s o r N o P D
Any Any Y es PD
*Nontarget lesions include ascites and peritoneal thickening, which are not measurable according to RECIST.
†Unequivocal progression in nontarget lesions may be accepted as disease progression.
CR, Complete response; PD, progressive disease; PR, partial response; SD, stable disease.
TABLE 3. Best overall response in patients with measurable disease and who are also evaluable by CA 125
Target
Lesion * Nontarget †New
Lesion CA 125Overall Best
Response
CR CR No Normal CR Best RECIST 1.1 response for
CR and PR also requires it to
be confirmed and maintained
for at least 28 days if response
is primary end pointCR Non-CR Non-PD No Not PD PR
CR CR No PR but not normal PR
CR NE No PR PR
PR Non-PD or NAE No Not PD PR
NAE Non-PD No PR PR
PD or New 928 days from CA 125 PR ‡ PR PR
SD§ Non-PD No PR PR
SD§ Non-PD or NAE No Not PR and not PD SD
PD or New e28 days From CA 125 PR ‡ PR PD
PD Any Y es or No Any PD
Any PD Y es or No Any PD
Any Any Y es Any PD
A n y A n y Y e so rN o P D P D
*Target lesions include up to 5 measurable lesions (2 per organ) as defined by RECIST 1.1.
†Nontarget lesions include ascites and peritoneal thickening which are not measurable according to RECIST 1.1.
‡Patients who have a CA 125 response that occurs more than 28 days from PD according to RECIST 1.1 are considered a PR, according
to best response, but PD if the RECIST 1.1 PD is within 28 days of CA 125 response.
§The protocol should specify the minimum time interval between 2 measurements for classification as stable disease.
NE, Not evaluated; NAE, not all evaluated.International Journal of Gynecological Cancer &Volume 21, Number 2, February 2011 Response and Progression of Ovarian Cancer
*2011 IGCS and ESGO 421
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criteria, the date of response will be the date of the earlier of
the 2 events if this approach to combined response reporting
is to be used. In the combined assessment of CA 125 and
RECIST 1.1 response, the following algorithm applies whendetermining the best overall response. If patients have pro-
gressive disease (PD) according to RECIST 1.1 within 28 days
of CA 125 response, they are classified as having PD. If the
PD according to RECIST 1.1 is longer than 28 days before or
after the CA 125 response, they are classified as having partial
response. Patients whose best response according to RECIST
1.1 is stable disease but who have a CA 125 response are
classified as CA 125 responders.
REPORTING OF RESPONSE ACCORDING TO
BOTH RECIST 1.1 AND CA 125 CRITERIA
Responses should be reported separately for both
RECIST 1.1 and CA 125 response as shown in the hypo-
thetical example in Table 4.
Definition of Progression on Therapy
and Recurrence After Therapy According
to CA 125
Progression (PD) is conventionally defined according to
RECIST 1.1 but can also be based on serum CA 125 (defined
below). However, in assigning the date of progression, PD by
objective change in tumor size should always take precedence
over CA 125 should it occur first. If measurable disease is
reducing in size during treatment but the CA 125 results sug-
gest progression (as defined below), the patient should con-
tinue to receive protocol treatment. If measurable disease is
stable but CA 125 indicates confirmed progression over atTABLE 4. Example of reporting RECIST, CA-125, and
combined response
RECISTCA 125 Response
Yes No or PD N/E Total RECIST
CR* 4 00 4
PR 3 11 5
SD 3 12 1 16
PD 0 8 2 10
NE 3 52 1 0
Total CA 125 13 26 6 Total entered = 45
In the above example, the RECIST 1.1 response rate is 9 (25.7%)
of 35 RECIST 1.1 evaluable patients, the CA 125 response rate is
13 (33%) of 39 CA 125 evaluable patients, and the combined overall
response rate (either RECIST or CA 125 response) is 15 (35%) of 43.
*RECIST 1.1 includes normalization of CA 125 to achieve CR
(Table 3).
Bolded numbers, CA 125 responders; bolded and italicized
numbers, both RECIST and CA 125 responders; italicized numbers,
RECIST responders.
TABLE 5. Definition of progression after first-line therapy in ovarian cancer as proposed by the GCIG
GCIG
Subcategorized
GroupRECIST
Measurable/Nonmeasurable
Disease CA 125
A Compared to baseline (or lowest sum
while on study if less than baseline),
a 20% increase in sum of diameters
(RECIST 1.1 definition)A
N
DCA 125 Q2/C2ULRR documented on 2 occasions*
orDate of PD: first date of the CA 125 elevation to
Q2/C2ULRR
Any new lesions (measurable or
nonmeasurable)/
or
Unequivocal increase in nontarget disease
Date of PD: date of documentation of
increase or new lesions
B As for A O CA 125 Q2/C2nadir value on 2 occasions*
R
Date of PD: first date of the CA 125 elevation to
Q2/C2nadir value
C As for A As for A
GCIG groups A, B, and C defined above.
CA 125 levels sampled after patients received mouse antibodies (unless the assay used has been shown not to be influenced by human
antimouse antibody4,5) or if there has been medical and/or surgical interference with their peritoneum or pleura during the previous 28 days
should not be taken into account.
*Repeat CA 125 any time but normally not less than 1 week after the first elevated CA 125 level.
ULRR, upper limit of response range.Rustin et al International Journal of Gynecological Cancer &Volume 21, Number 2, February 2011
422 *2011 IGCS and ESGO
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least 4 weeks, some protocols may advise changing protocol
treatment, unless there is the possibility that the therapy could
be slowing the rate of rise of CA 125. If patients are having
routine CA125 measurements as part of follow-up, the date
of progression is likely to be several months earlier than
symptoms or signs of progression develop.6Therefore, when
categorizing patients according to time to progression, it is
necessary to specify how the date of progression was defined
(CA 125 alone, CA125 and symptoms, and RECIST). Proto-
cols will need to specify that these data have to be collected.
EVALUATION OF PROGRESSION
ACCORDING TO CA 125
Progression or recurrence based on serum CA 125 levels
will be defined on the basis of a progressive serial elevation of
serum CA 125 according to the following criteria and Table 5:
A. Patients with elevated CA-125 pretreatment and nor-
malization of CA-125 must show evidence of CA-125
greater than, or equal to, 2 times the upper limit of the
reference range on 2 occasions at least 1 week apart or
B. Patients with elevated CA-125 before treatment, which
never normalizes, must show evidence of CA-125 greater
than, or equal to, 2 times the nadir value on 2 occasions
at least 1 week apart or
C. Patients with CA-125 in the reference range before
treatment must show evidence of CA-125 greater than,
or equal to, 2 times the upper limit of the reference range
on 2 occasions at least 1 week apart.
CA 125 progression will be assigned the date of the
first measurement that meets the criteria as noted. Patientsare not evaluable by CA 125 if they have received mouse
antibodies (unless the assay used has been shown not to
be influenced by human antimouse antibody4,5) or if there
has been medical and/or surgical interference with their
peritoneum or pleura (eg, paracentesis) during the previous
28 days.
A patient may be declared to have PD on the basis
of either the objective RECIST 1.1 criteria or the CA 125
criteria. The date of progression will be the date of the earlier
of the 2 events if both are documented.
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evaluation criteria in tumors: revised RECIST guideline
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2010;376:1155 Y1163.International Journal of Gynecological Cancer &Volume 21, Number 2, February 2011 Response and Progression of Ovarian Cancer
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