Surveillance of patients after initial treatment of ovarian cancer Angiolo Gadducci Department of...

Surveillance of patients after initial treatment

of ovarian cancer

Angiolo Gadducci

Department of Gynecology and Obstetrics, Unit of

Gynecologic Oncology, University of Pisa

Rome October 5-6 2007

Mediterranean School of Oncology

Highlights in the management of ovarian cancer

Carcinoma of the ovary:5-year survival by FIGO stage

FIGO Stage Pts 5-year survival (%)Ia 467 89.3Ib 58 64.8Ic 560 78.2IIa 73 79.2IIb 105 64.3IIc 206 68.2IIIa 120 49.2IIIb 251 40.8IIIc 1653 28.9IV 511 13.4(FIGO Annual Report 25, patients treated in 1996-98)

Follow-up of patients with epithelial ovarian cancer (EOC)

Analysis of recurrence: rates and sites

Early stage patients

Advanced stage patients who achieved a complete response

Examinations of patient surveillance

Physical examination

Tumor marker assay

Ultrasound (US)

Computed tomography (CT)

Magnetic resonance imaging (MRI)

PET/CT

Follow-up protocols

PET

Adjuvant treatment for early OC

Sites of recurrences Trial 1 Trial 2

CDDP vs observation CDDP vs 32P

Pelvis only 8 (38.1%) 18 (47.4%)

Nodes only 2 (9.5%) 3 (7.4%)

Multiple abdominal 11 (52.4%) 17 (44.7%)

or distant metastases

GICOG, 1995

224 pts with early EOC: sites of recurrence

SITES Patients

N. % Pelvis

10 25.6

Abdomen 12 30.8

Nodes 1 2.6

Distant 5 12.8

Pelvis + Abdomen 7 17.9

Pelvis + Nodes 4 10.3

39

SITES Patients

N. % Pelvis

10 25.6

Abdomen 12 30.8

Nodes 1 2.6

Distant 5 12.8

Pelvis + Abdomen 7 17.9

Pelvis + Nodes 4 10.3

39

CTF 1997

VariableAdjuvant chemotherapy

(N = 224)Observation

(N = 224)Total

(N = 448)

No recurrence, n (%) 184 (82) 164 (73) 348 (78)

Recurrence, n (%) 40 (18) 60 (27) 100 (22)

Pelvic 14 (6) 20 (9) 34 (8)

Extrapelvic 20 (9) 28 (13) 48 (11)

Both (pelvic + extrapelvic) 6 (3) 12 (5) 18 (4)

Impact of adjuvant chemotherapy and surgical staging in early-stage EOC : EORTC/ACTION trial.

Trimbos, 2003

Disease-free survival in patients with stage I OC

pts DFS 5-y OS 7-y p value

FIGO stage

Ia 111 93.0% 91.6%

Ib 21 83.0% 83.0%0.0006

Ic 92 69.7% 66.2%

Histological type

Endometroid + muc 91 81.9% 80.3%

Serous 98 83.3% 79.4%ns

Clear cell 14 62.3% 62.3%

Histological grade

G1 95 94.3% 92.8%

G2 77 76.9% 76.9%0.0001

G3 36 57.2% 47.3%

CTF , 1997

Variables predictive of disease-free survival in patients with stage I OC: Cox model

Variables Wald 2 p value risk ratio 95% CI

G2 5.75755 0.0164 2.831 1.210-6.624

G3 22.03627 0.0001 7.725 3.29.-18.140

CTF , 1997

Time to recurrence from surgeryPts

n %<6 1 2.6

6 < t < 12 7 17.9

12 < t < 24 8 20.5

24 < t < 36 8 20.5

36 < t < 48 7 17.9

48 < t < 60 3 7.7

>60 5 12.8

94

CTF, 1997

224 pts with early EOC: times of recurrence


Analysis of recurrence: rates, times, sites


Advanced stage patients who achieved a complete responseExaminations of patient surveillance


Tumor marker assay

Ultrasound (US)



PET/CT

Follow-up protocols

PET

Second-look (SL)No convincing data are available showing that SL improves the chances for cure or prolongs survival.

A lack of randomized prospective studies directly evaluating the therapeutic benefits of a SL procedure restricts its role to research protocols or to selected cases

Patients with primary suboptimal primary surgery appear to achieve a survival benefit from SL (early identification and treatment of residual disease) Rahaman 2005

The value of secondary cytoreductive surgery at the time of SL is still debated

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Rahaman+J%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Rahaman+J%22%5BAuthor%5D

198 pts with advanced EOC who achieved a pathologic complete responses: site of recurrence

Sites Ptsn %

Pelvis 26 27.7

Abdomen 21 22.3

Nodes 7 7.4

Distant 14 14.9

Pelvis + abdomen 16 17.0

Abdomen +nodes 2 2.1

Pelvis + nodes 2 2.1

Pelvis + distant 1 1.1

Distant + nodes 2 2.1

Abdomen + distant 3 3.2

94 CTF, 1998

198 pts with advanced EOC who achieved a pathologic complete responses: times of recurrence

Time to recurrence from SL (momths)Pts

n %<6 7 7.4

6 < t < 12 21 22.3

12 < t < 24 29 30.9

24 < t < 36 13 13.8

36 < t < 48 12 12.8

48 < t < 60 6 6.4

>60 6 6.4

94

CTF, 1998

PFS in 198 pts with stage III-IV OC after negative SL (I)

pts pts with PFS 5-y OS 7-y p value

recurrences

Age <50 41 17 59.4% 50.8>50 88 44 40.6% 40.6% 0.0519

FIGO stageIIIa 20 4 77.7% 77.7%IIIb 40 19 49.5% 39.7% 0.0080IIIc + IV 132 71 42.0% 40.2%Histological typeEndometroid 22 12 47.7% 80.3%Serous + oth 98 70 44.9% 79.4%nsCc + muc + und 34 12 56.7% 49.6%Histological grade

G1 24 5 87.1% 81.3%G2 70 35 45.9% 42.8% 0.0021G3 87 50 36.3% 33.7%

CTF, 1998

PFS in 198 pts with stage III-IV OC after negative SL (II)

pts pts with PFS 5-y OS 7-y p value

recurrences

RD after 1st surgery <1 cm 87 31 62.2% 57.31-2 cm 49 28 41.1% 37.3%>2 cm 56 35 32.0% 32.0% 0.0038

1st CTSingle CDDP 18 8 49.9% 49.7%Or CBDCA CDDP or CBDCA- 162 79 47.7% 44.0%nsbased CTOther 12 7 41.7% 41.7%SLLaparoscopy 34 22 28.9% 28.9%Laparotomy 158 72 51.3% 48.0% 0.0061

CTF, 1998

Variables predictive of PFS in patients with stage III-IVOC after negative SL: Cox model

Variables Wald 2 p value risk ratio 95% CI

RD 1-2 cm 5.65351 0.0174 1.877 1.117-3.156

RD > 2 cm 9.54639 0.0020 2.156 1.324-3.511

G2 5.33134 0.0209 2.386 1.140-4.990

G3 9.53244 0.0020 3.118 1.515-6.416

SL 5.85793 0.0155 1.826 1.121-2.973

CTF, 1998

Few formal guidelines exist regarding the surveillance of EOC pts

The objective of follow-up in pts who have already been treated with primary cytoreductive surgery and first-line

chemotherapy is not clear, as recurrent disease continues to be a therapeutic dilemma.

The vast majority of women with relapses will eventually succumb to their disease. The primary goal of salvage therapy

therefore is to maximize disease-free survival and quality of life.

It is not clear whether early detection of recurrent disease is beneficial.

The follow-up of EOC: general consideration

Vaidya, Curtin 2003






Tumor marker assay

Ultrasound (US)



PET/CT

Follow-up protocols

PET

Patients and methods: Retrospective analysis of 52 pts with recurrent EOC.

Clinical examination and CA 125 assay were compared to US findings.

Pathological findings

Physical examination 73%

CA 125 assay 85%

US 54%

CA 125, physical and US findingsin follow-up of EOC patients

Wu 2003

CA 125, physical and radiological findingsin follow-up of EOC patients

Patients and methods: Retrospective analysis of 58 pts with recurrent EOC.

Clinical examination and CA 125 assay were compared to radiologic findings. pts Pathological findings

Physical interview and physical examination 58 78%

CA 125 assay 54 83%

US 47 70%

CT 42 80%

Physical examination and CA 125 54 98%

In pts with a pelvic recurrence, physical examination had the

highest SE compared to US and CT scan

Fehm 2005

Cut-off >35 u/ml > 65 u/ml

Sensitivity 68-94% 50-88%

Specificity 67-94% 83-99%

(collected series)

CA125 in the diagnostic evaluation of ovarian masses

Histotype CA125 >35 U/ml CA125 >65 U/ml

Mucinous 15/22 68.2% 12/22 54.5%

p<0.0115

Non mucinous 109/125 87.2% 102/125 81.6%

Total 124/147 114/147

Sensitivity 84.4% 77.6%

Incidence of presurgical elevated serum levels of CA125 in pts with EOC: Relationship with histotype

Gadducci et al., 1995

Elevated CA125 levels at the 82-96%clinical detection of progression

Elevated CA125 levels before 56-94%clinical detection of progression

Serum CA125 assay in the early detection of progression

Collected series

A rise of CA 125:

of 50% Krebs et al. 1986

of 100% Bast et al. 1983

just above the cut-off van der Burg et al. 1986

a doubling of CA 125 from

the upper limit of normal Rustin et al. 1996

Defining progression of EOC during

follow-up according to CA 125

Rise from < 30 to > 60 Two consecutive values > 60

TP 73 73 FP 4 1 TN 42 42 FN 12 14

SE 85.9% 83.9% SP 91.3% 97.7% PPV 94.8% 98.6% NPV 77.8% 75.0% Median lead time 63 days 63 days

Ability of serum CA125 to predict early progression in 131 patients by using a doubling

of the normal cut-off (30 U/ml)

Rustin et al., 1996

Recurrent epithelial ovarian cancer

ELEVATED CA-125ELEVATED CA-125No evidence of clinical or radiological disease in asymptomatic patients

• Late recurrence (>24 mos)

• Platinum sensitive• Platinum resistant• Platinum refractory

Measurable or Measurable or evaluable diseaseevaluable diseasesymptomatic patients

Response to CT can be better in patients with small lesions and good PS

Early administration of CT at the time of CA125 elevation is associated with a greater anxiety due to an earlier knowledge of disease status

Drug related toxicities can be heavier the lower is time interval from the first CT

Serum CA125 elevation in asymptomatic patients

Intergroup phase III study comparing early versus delayed chemotherapy in EOC patients with raised CA125 levels and no

evidence of disease

EORTC Gynaecologic Cancer Cooperative Group (GCCG)

(Dept. Gynecol. Obstet. and Dept. Oncol., Univ. PISA)

EORTC 55955

Marker Elevated marker Positive correlation between at diagnosis marker levels and disease course

CA125 35 188/225 instances 87.4%

CA19.9 16 61/80 instances 76.3%

CA15.3 24 87/122 instances 71.3%

TAG-72 30 27/167 instances 76.0%


The relationship between tumor markers and the clinical course of disease

Gadducci al. 1993

Marker Pts elevatedCorrelation of Pts with Pts withmarker at diagnosis marker levels s progression rising

markers with clinical after CT before clinical

. disease course progression

CA125 35/40 87.5% 3 or 8 3 CA19.9 30/40 75.0% 2

CA125 100/118 84.7% 9 or 23 9 CA15.3 83/118 70.3% 6

CA125 123/144 85.4% 10 or 25 10 TAG-72 107/144 74.3% 8


Correlation of CA125 and each of the other antigens with disease status in patients

with elevated multiple markers at diagnosis

Gadducci et al. 1993






Tumor marker assay

Ultrasound (US)



PET/CT

Follow-up protocols

PET

pts SE SP PPV NPV Clarke-Pearson 1986 46 32% 77% 79% 30%Silverman 1988 64 40% 99% 96% 87% Reuter 1989 35 84% 88% 89% 83%De Rosa 1995 58 47% 87% 84% 53%Topuz 2000 52 50% 100% 100% 76%Cho 2002 21 54% 99% 97% 91%Fazio 2003 25 70% 83% 89% 59% SE is dependent on site and size of tumor lesion (good for N , average for pelvic and omental lesion, and low for other peritoneal locations; lesions < 1.5 are often undetectable)

CT accuracy in the detection of persistent disease at SL

CT accuracy in the detection of recurrent EOC

pts SE SP DA Kainz, Prayer 1994 24 63% 94% 83%Kubik-Huck 2000 11 40% 50% 43% Cho 1992 21 54.5 99.6% 91.7% Garcia-Velloso 2003 19 47% 43% -Havrileski 2005^ 68% 58% 59% Grabiec 2006 27 56% 60% 52%Sebastian 2007 51 92% 60% 83% ^Pooled analyses of 10 studies

Patients and methods: 127 advanced EOC pts undergone surgery and chemotherapy and follow-ed with radiologic

imaging

82 (65%) pts had had at least one chest CT scan, with > 50% having

had > 3 scans.

32 (39%) patients had no radiologic evidence of disease.

28 (34%) had disease in the abdomen/pelvis, but not in the chest.

18 (22%) had both chest and abdominal/pelvic CT scans that

indicated disease. In all of these patients, abdominal/pelvic disease

had appeared on scans before spreading to the chest.

4 (5%) of the patients had isolated chest disease.

Value of chest CT scans in routine EOC follow-up

Sella 2001

Patients and methods: 96 EOC pts who had at least one CT scan of the chest, abdomen, and pelvis during follow-up. A total of 266 CT scans were obtained 41 (41.7%) of the 96 pts had metastatic chest disease on one or more scans.

In the absence of disease in abdomen/pelvis, chest progression was seen in 6 (2.7%) of the 226 follow-up CT scans. 5 of the six pts had rising CA-125 levels.


Dachman 2001

Pulmonary metastases are rare (6%) and usually preceded by recurrent

disease in the abdomen or pelvis.

Chest CT is not indicated in the routine follow-up

Chest CT should be performed for those patients with elevated serum

CA125 but without evidence of abdominal / pelvic disease


Sella 2001

pts SE SP PPV NPV

Kubich-Huck 200 9 86% 100% 100%

67%

Low 69 91% 87% 96% 72%Balestrieri 2002 22 84% 100% 100% 50%

Recurrent EOC: MRI

pts SE SP PPV NPV

Ricke 200 39

upper abdomen 67% 89% 87%

70%

bowel 72% 70% 87% 47%

lower pelvis 73% 83% 73% 83%

abdominal wall 83% 60% 77%

69%

lymph node 67% 86% 93% 46%

carcinomatosis 69% 74% 65% 77%

Recurrent EOC: MRI

Patients and Methods: 24 pts treated for EOC who were prospectively examined by US CT and MRI

SE SP PPV NPV DA US 50% 100% 100% 80% 83% CT 63% 94% 83% 83% 83%MRI 75% 94% 86% 88% 88%CT + MRI 75% 88% 75% 88% 83%

CT is the primary imaging modality to prove macroscopic recurrence, and MRI should be performed in women with questionable macroscopic recurrent tumor and negative CT

US, CT, and MRI accuracy in the detection of recurrent EOC

Kainz, Prayer 1994







Tumor marker assay

Ultrasound (US)



PET/CT

Follow-up protocols

PET

pts SE SP PPV NPV

Kubich-Huck 2000 10 100% 50% 90%

89%

Nakamoto 2001 12 80% 50% 89% 33%

Yen 2001 24 91% 92% - -

Chang 2002 28 95.0% 87% - -

Torizuka 2002 25 80% 100% 100% 55%

Takekuma 2005 29 85% 100% 100% 43%

Recurrent EOC: PET

PET MRI/CT CA125 n. SE SP SE SP SE SP Torizuma 25 80% 83% 55% 83% 75% 100% 2002

Yen 24 91% 92% 91% 46% 91% 77%

2001

GarciaVeloso 19 100% 90% 47% 43% 84% 86%2003

FDG-PET, convetional imaging, and CA 125 for detectionof recurrent EOC in the presence of clinical suspicion

Patients and methods: 106 PET performed in 54 EOC pts followed- up after primary treatment

58 PET performed in pts with suspected recurrence and 48 in clinically-free

pts PET SE SP

Whole series 83% 83% Pts with suspected recurrence 94% Pts with rising CA125 alone 96% Clinically-free pts 65% The median relapse-free interval after a negative PET scan was 20 months

PET in the follow-up of EOC

Zimmy 2001

Patients and methods: A total of 90 PET studies and the associated CA 125 values (cut-off < 35 U/ml) were available in 71 pts during the follow-up after primary therapy for EOC .

PET CA 125 levels median , range Normal findings (23 studies) 13.3 U/ml ( 4.2-168 U/ml)Abnormal findings (67 studies) 166.7 U/ml (13.3-4,060 U/ml) p< 0.001

With one exception, there were no normal PET above CA 125 levels of 30 U/mlBetween 20 and 30 U/ml PET was positive in 4/7 studies.

a PET indication is worthwhile at CA 125 levels of approximately 30 U/ml.

Recurrent EOC: PET

Menczel 2004

Studies published between 1966 and 2003 were identified using MEDLINE database. Two reviewers independently abstracted data regarding SE and SP of PET. 10 studies met inclusion criteria for full text review.

Pooled SE SP PET 90% 86% CT/MRI 68% 58%CA 125 81% 83%Negative CA125 PET 54% 73% Negative conventional imaging Rising CA125 PET 96% 80% Negative conventional imaging

Recurrent EOC: PET

Havrilesky 2005







Tumor marker assay

Ultrasound (US)



PET/CT

Follow-up protocols

PET

PET suffers from a lack of anatomic resolution . Combined PET/CT devices can acquire PET and CT images that are contemporaneous in order to localize areas of increased 18FDG uptake with improved anatomic specificity

Charron 2000 Martinez-Roman 2005

Martinelli 2000 Bristow 2005

Makhija 2002 Hauth 2005

Vergote 2003 Sebastian 2007

Fazio 2004 Chung 2007

Pannu 2005 Thrall 2007

PET/CT

pts SE SP PPV NPVNanni 2005 41 88% 71% 93% 55% Pannu 2005* 16 73% 40% 73% 40%

Bristow 2005 22 83% 75% 94% 50%

Sebastian 2007 51 97% 80% - -

Chung 2007 77 93% 97% 95% 98%

Thrall 2007 22 94% 100% 100% 87%

*PET/CT detected 100% of 7 positive N , 13% of 23 peritoneal lesions < 1 cm , and 50% of peritoneal lesions > 1 cm

Recurrent EOC: PET/CT

Patients and methods: 14 pts with rising CA125 , and negative or equivocal conventional CT imaging > 6 months after primary therapy were retrospectively identified as having recurrent disease limited to retroperitoneal N by combined PET/CT and underwent surgical reassessment Results: 11 (78.6%) pts had disease in N targeted by PET/CT. Of 143 N retrieved, 59 contained recurrent disease SE SP NPV PPV DA PET: 40.7% 94.0% 82.8% 69.3% 72.0% PET/CT failed to identify microscopic disease in 59.3% of pathologically positive N

Combined PET/CT for detecting recurrent EOC limited to retroperitoneal lymph nodes

Bristow 2005

PET/TC is able to detect unusual

supradiaphragmatic lymphatic diffusion of EOC (ie

supraclavicular nodes)

Fanti 2006

Recurrent EOC: PET/CT

Patients and methods: 22 EOC pts with rising CA125 and negative or equivocal CT findings > 6 months after primary therapy who underwent PET/CT followed by surgical reassessment

SE PPV DA Ability of PET/CT in detectingrecurrent disease > 1 cm at surgery 83.3% 93.8% 81.8%

PET/CT in clinically occult recurrent EOC

Bristow 2003







Tumor marker assay

Ultrasound (US)



PET/CT

Follow-up protocols

PET

Lo stato dell’arte• Attualmente si definisce corretto il follow-up che si Attualmente si definisce corretto il follow-up che si compone dicompone di :: anamnesi patologica prossimaanamnesi patologica prossima

esame obiettivo generale e pelvicoesame obiettivo generale e pelvico : : permette di diagnosticare una recidiva in sede pelvica, presente nel 60% dei casi di ripresa di malattia1

Dosaggio Ca 125 + esame clinico generale + visita Dosaggio Ca 125 + esame clinico generale + visita ginecologica = identificazione del 90% delle pazienti con ginecologica = identificazione del 90% delle pazienti con recidivarecidiva22

2 . Rustin GJS et al . Tumor markers. Ann Oncol 1993; 4 (Suppl 4): 71-771. PNLG – Diagnosi e terapia del carcinoma ovarico Cap. 8 : p69-73

dosaggio del Ca125dosaggio del Ca125 : : il suo incremento costituisce il primo indicatore di recidiva in circa il 70% delle pazienti e può anticipare l’evidenza clinica di circa 4 mesi1

esami strumentali radiologiciesami strumentali radiologici : : es. ecografia TV, ecografia addome completo, TAC o RMN o PET

Specific guidelines for surveillance of EOC of this disease are controversial, partly because evidence to support such guidelines

is scant and partly because the management of identified recurrences continues to be of minimal success.

Whether early detection actually can make a difference is not

necessarily made clear in the literature.

Most of the recent literature involving detection of recurrent EOC addresses the use of PET.

While radiological technology improvements are noteworthy, their potential impact on surveillance appears to be limited at this

time . Unsatisfactory Low SE and SP, along with expense, continue to be limiting

New modalities in detection of recurrent EOC

Tammela, Lele, Curr Opin Obstet Gynecol 2004

What Is Appropriate Follow-up After Primary TherapyWhat Is Appropriate Follow-up After Primary Therapy??

• The ideal follow-up of asymptomatic women who have completed primary debulking surgery and chemotherapy and have no clinical evidence of disease is unclear.

NIH Consensus Statement. 1994 Apr 5-7;12(3):1-30.

• The follow-up of asymptomatic patients after primary therapy should include routine complete history, physical, rectovaginal routine complete history, physical, rectovaginal

pelvic exam, and CA 125pelvic exam, and CA 125.. Although optimal intervals for monitoring optimal intervals for monitoring

have not been determined,have not been determined, current practice is to follow the patient every 3 to 4 months. After 2 years, less frequent follow-up intervals can be considered. CA 125 has been shown to be a reliable method of monitoring for early detection of recurrence in women whose CA 125 was elevated preoperatively. • A rising CA 125 is a predictor of relapse; however, a negative CA 125 does not exclude the presence of disease.

•exams done on a routine basis have not been shown to improve exams done on a routine basis have not been shown to improve the detection of recurrencethe detection of recurrence. Their use should be individualized.

Follow-Up program: MD Anderson– University of Texas – Ovarian cancer guidelines

Clinical and gynecological examination every 3 Clinical and gynecological examination every 3

months X 4 times then every 4 months for 3 times, months X 4 times then every 4 months for 3 times,

then every 6 months for 6 times then every 6 months for 6 times

Ca125 at any examination (if elevated at diagnosis)Ca125 at any examination (if elevated at diagnosis)

Abdominal/pelvic CT scan when symptoms /signs Abdominal/pelvic CT scan when symptoms /signs

appear appear

Opzioni Grado di raccomandazione

Visita, CA 125, ecografia ogni 3 mesi x 1-2 anno A ogni 4 mesi x 3 anno

ogni 6 mesi x 4-5 annoogni 12 mesi oltre 5 anno

Rx torace ogni 6 mesi x 1-2 anno BOgni 12 mesi successivamente

TC: annuale C

PET in caso di elevazione asintomatica del CA125 C

Algoritmo di Follow-Up: Linee guida Istituto Tumori Toscano (ITT)

Clinical history Physical examination

USCA 125

Suspicious symptoms Abnormal

findings

Rising levels

CT scan or MRI

Additional investigation is needed

negative

Close F/U

positive

Therapy

CT scan or MRI

positivenegative

Chest imaging

positive negative

PET or TC/PET

positivenegative

Close F/U or immediate therapy

Follow-up procedures: CTF proposal

Surveillance of patients after initial treatment of ovarian cancer Angiolo Gadducci Department of...

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