1. Mediterranean School of Oncology
Highlights in the management of ovarian cancer
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

2. Carcinoma of the ovary:5-year survival by FIGO stage
FIGO Stage Pts 5-year survival (%) Ia Ib Ic
IIa
IIb
IIc
IIIa
IIIb
IIIc IV
(FIGO Annual Report 25, patients treated in )

3. 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
PET/CT
Follow-up protocols

4. Adjuvant treatment for early OC
Sites of recurrences Trial 1 Trial 2
CDDP vs observation CDDP vs 32P
Pelvis only (38.1%) 18 (47.4%)
Nodes only (9.5%) 3 (7.4%)
Multiple abdominal (52.4%) 17 (44.7%)
or distant metastases
GICOG, 1995

5. 224 pts with early EOC: sites of recurrence
SITES Patients N % Pelvis
Abdomen
Nodes
Distant
Pelvis + Abdomen
Pelvis + Nodes
CTF 1997

6. Adjuvant chemotherapy (N = 224)
Impact of adjuvant chemotherapy and surgical staging in early-stage EOC : EORTC/ACTION trial.
Variable
Adjuvant 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
28 (13)
48 (11)
    Both (pelvic + extrapelvic)
6 (3)
12 (5)
18 (4)
Trimbos, 2003

7. Disease-free survival in patients with stage I OC
pts DFS 5-y OS 7-y p value
FIGO stage
Ia % 91.6%
Ib % 83.0%
Ic % 66.2%
Histological type
Endometroid + muc % 80.3%
Serous % 79.4% ns
Clear cell % 62.3%
Histological grade
G % 92.8%
G % 76.9%
G % 47.3%
CTF , 1997

8. Variables predictive of disease-free survival
in patients with stage I OC: Cox model
Variables Wald 2 p value risk ratio 95% CI G G
CTF , 1997

9. 224 pts with early EOC: times of recurrence
Time to recurrence from surgery Pts
n %
<
6 < t <
12 < t <
24 < t <
36 < t <
48 < t <
> 94
CTF, 1997

10. Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, 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
PET/CT
Follow-up protocols

11. 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

12. 198 pts with advanced EOC who achieved a pathologic complete responses: site of recurrence
Sites Pts
n %
Pelvis
Abdomen
Nodes
Distant
Pelvis + abdomen
Abdomen +nodes
Pelvis + nodes
Pelvis + distant
Distant + nodes
Abdomen + distant 94
CTF, 1998

13. Time to recurrence from SL (momths) Pts n % <6 7 7.4
198 pts with advanced EOC who achieved a pathologic complete responses: times of recurrence
Time to recurrence from SL (momths) Pts
n %
<
6 < t <
12 < t <
24 < t <
36 < t <
48 < t <
> 94
CTF, 1998

14. 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
< % 50.8
> % 40.6%
FIGO stage
IIIa % 77.7%
IIIb % 39.7%
IIIc + IV % 40.2%
Histological type
Endometroid % 80.3%
Serous + oth % 79.4% ns
Cc + muc + und % 49.6%
Histological grade
G % 81.3%
G % 42.8%
G % 33.7%
CTF, 1998

15. 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 % 57.3
1-2 cm % 37.3%
>2 cm % 32.0%
1st CT
Single CDDP % 49.7%
Or CBDCA
CDDP or CBDCA % 44.0% ns
based CT
Other % 41.7% SL
Laparoscopy % %
Laparotomy % 48.0%
CTF, 1998

16. Variables predictive of PFS in patients with stage III-IV
OC after negative SL: Cox model
Variables Wald 2 p value risk ratio 95% CI
RD 1-2 cm
RD > 2 cm G G SL
CTF, 1998

17. The follow-up of EOC: general consideration
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.
Vaidya, Curtin 2003

18. Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, 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
PET/CT
Follow-up protocols

19. CA 125, physical and US findings in follow-up of EOC patients
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 %
CA 125 assay %
US %
Wu 2003

20. CA 125, physical and radiological findings
in 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 %
CA 125 assay %
US %
CT %
Physical examination and CA %
In pts with a pelvic recurrence, physical examination had the highest SE compared to US and CT scan
Fehm 2005

21. CA125 in the diagnostic evaluation of
ovarian masses
Cut-off
>35 u/ml > 65 u/ml
Sensitivity % %
Specificity % %
(collected series)

22. Incidence of presurgical elevated serum levels of
CA125 in pts with EOC: Relationship with histotype
Histotype CA125 >35 U/ml CA125 >65 U/ml
Mucinous / % / %
p<0.0115
Non mucinous / % / %
Total / /147
Sensitivity % %
Gadducci et al., 1995

23. Serum CA125 assay in the early detection of progression
Elevated CA125 levels at the %
clinical detection of progression
Elevated CA125 levels before %
clinical detection of progression
Collected series

24. Defining progression of EOC during follow-up according to CA 125
A rise of CA 125:
of 50% Krebs et al. 1986
of 100% Bast et al
just above the cut-off van der Burg et al
a doubling of CA 125 from
the upper limit of normal Rustin et al. 1996

25. Ability of serum CA125 to predict early
progression in 131 patients by using a doubling
of the normal cut-off (30 U/ml)
Rise from < 30 to > Two consecutive values > 60 TP FP TN FN
SE % %
SP % %
PPV % %
NPV % %
Median lead time days days
Rustin et al., 1996

26. Recurrent epithelial ovarian cancer
ELEVATED CA-125
No evidence of clinical or
radiological disease in
asymptomatic patients
Measurable or evaluable disease
symptomatic patients
Late recurrence (>24 mos)
Platinum sensitive
Platinum resistant
Platinum refractory

27. Serum CA125 elevation in asymptomatic 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

28. EORTC Gynaecologic Cancer Cooperative Group (GCCG)
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)

29. The relationship between tumor markers
and the clinical course of disease
Marker Elevated marker Positive correlation between at diagnosis marker levels and disease course
CA /225 instances %
CA /80 instances %
CA /122 instances %
TAG /167 instances %
(Dept. Gynecol. Obstet. and Dept. Oncol., Univ. PISA)
Gadducci al. 1993

30. Correlation of CA125 and each of the other
antigens with disease status in patients
with elevated multiple markers at diagnosis
Marker Pts elevated Correlation of Pts with Pts with
marker at diagnosis marker levels s progression rising markers with clinical after CT before clinical
disease course progression
CA / % or
CA / %
CA / % or
CA / %
CA / % or
TAG / %
(Dept. Gynecol. Obstet. and Dept. Oncol., Univ. PISA)
Gadducci et al. 1993

31. Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, 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
PET/CT
Follow-up protocols

32. CT accuracy in the detection of persistent disease at SL
pts SE SP PPV NPV
Clarke-Pearson % % % %
Silverman % % 96% 87%
Reuter % % 89% 83%
De Rosa % % % %
Topuz % % % %
Cho % 99% 97% 91%
Fazio % % % % 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)

33. CT accuracy in the detection of recurrent EOC
pts SE SP DA
Kainz, Prayer % % 83%
Kubik-Huck % % %
Cho % %
Garcia-Velloso % % -
Havrileski 2005^ 68% % %
Grabiec % 60% 52%
Sebastian % % %
^Pooled analyses of 10 studies

34. Value of chest CT scans in routine EOC follow-up
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.
Sella 2001

35. Value of chest CT scans in routine EOC follow-up
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

36. Value of chest CT scans in routine EOC follow-up
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

37. Recurrent EOC: MRI pts SE SP PPV NPV
Kubich-Huck % % 100% 67%
Low % 87% 96% 72%
Balestrieri % % 100% 50%

38. Recurrent EOC: MRI pts SE SP PPV NPV Ricke 200 39
upper abdomen 67% % 87% 70%
bowel 72% 70% 87% 47% lower pelvis 73% 83% 73% 83%
abdominal wall 83% 60% 77% 69%
lymph node 67% % 93% 46%
carcinomatosis 69% % 65% 77%

39. US, CT, and MRI accuracy in the detection of
recurrent EOC
Patients and Methods: 24 pts treated for EOC who were prospectively examined by US CT and MRI
SE SP PPV NPV DA
US % % % % %
CT % % % % %
MRI % % % % %
CT + MRI % % % % %
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
Kainz, Prayer 1994

40. Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, 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
PET/CT
Follow-up protocols

41. Recurrent EOC: PET pts SE SP PPV NPV
Kubich-Huck % % 90% 89%
Nakamoto % % 89% 33%
Yen % 92%
Chang % 87% Torizuka % % 100% 55%
Takekuma % % 100% 43%

42. FDG-PET, convetional imaging, and CA 125 for detection
of recurrent EOC in the presence of clinical suspicion
PET MRI/CT CA125
  n. SE SP SE SP SE SP
Torizuma % % % % % %  
Yen % % % % % %
2001
GarciaVeloso % % 47% % 84% %
2003

43. PET in the follow-up of EOC
Patients and methods: 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 % %
Pts with suspected recurrence 94%
Pts with rising CA125 alone %
Clinically-free pts %
The median relapse-free interval after a negative PET scan was 20 months
Zimmy 2001

44. Recurrent EOC: PET
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) U/ml ( U/ml)
Abnormal findings (67 studies) 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/ml
Between 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.
Menczel 2004

45. Recurrent EOC: PET
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 % %
CT/MRI % %
CA % %
Negative CA125 PET % %
Negative conventional imaging
Rising CA125 PET % %
Havrilesky 2005

46. Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, 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
PET/CT
Follow-up protocols

47. PET/CT
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 Martinez-Roman 2005
Martinelli Bristow
Makhija Hauth
Vergote   Sebastian
Fazio Chung
Pannu Thrall

48. Recurrent EOC: PET/CT pts SE SP PPV NPV Nanni 2005 41 88% 71% 93% 55%
Pannu * % % 73% %
Bristow % % 94% %
Sebastian % %
Chung % 97% 95% %
Thrall % 100%  100% %
*PET/CT detected 100% of 7 positive N , 13% of 23 peritoneal lesions < 1 cm , and 50% of peritoneal lesions > 1 cm  

49. Combined PET/CT for detecting recurrent EOC
limited to retroperitoneal lymph nodes
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: (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: % % % % %
PET/CT failed to identify microscopic disease in 59.3% of pathologically positive N
Bristow 2005

50. Recurrent EOC: PET/CT
PET/TC is able to detect unusual supradiaphragmatic lymphatic diffusion of EOC (ie supraclavicular nodes)
Fanti 2006

51. PET/CT in clinically occult recurrent EOC
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 detecting
recurrent disease > 1 cm at surgery % % %
Bristow 2003

52. Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, 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
PET/CT
Follow-up protocols

53. Lo stato dell’arte
Attualmente si definisce corretto il follow-up che si compone di :
anamnesi patologica prossima
esame obiettivo generale e pelvico : permette di diagnosticare una recidiva in sede pelvica, presente nel 60% dei casi di ripresa di malattia1
dosaggio 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 radiologici : es. ecografia TV, ecografia addome completo, TAC o RMN o PET
Dosaggio Ca esame clinico generale + visita ginecologica = identificazione del 90% delle pazienti con recidiva2
PNLG – Diagnosi e terapia del carcinoma ovarico Cap. 8 : p69-73
2 . Rustin GJS et al . Tumor markers. Ann Oncol 1993; 4 (Suppl 4): 71-77

54. New modalities in detection of recurrent EOC
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
Tammela, Lele, Curr Opin Obstet Gynecol 2004

55. What 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.
The follow-up of asymptomatic patients after primary therapy should include routine complete history, physical, rectovaginal pelvic exam, and CA 125. Although optimal intervals for monitoring 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 the detection of recurrence. Their use should be individualized.
NIH Consensus Statement Apr 5-7;12(3):1-30.

56. Follow-Up program:
MD Anderson– University of Texas – Ovarian cancer guidelines
Clinical and gynecological examination every 3 months X 4 times then every 4 months for 3 times, then every 6 months for 6 times
Ca125 at any examination (if elevated at diagnosis)
Abdominal/pelvic CT scan when symptoms /signs appear

57. Algoritmo di Follow-Up:
Linee guida Istituto Tumori Toscano (ITT)
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 anno ogni 12 mesi oltre 5 anno
Rx torace ogni 6 mesi x 1-2 anno B Ogni 12 mesi successivamente
TC: annuale C
PET in caso di elevazione
asintomatica del CA125 C

58. Follow-up procedures: CTF proposal
CA 125
Clinical history
Physical examination US
Rising levels
Suspicious symptoms
Abnormal findings
CT scan or MRI
CT scan or MRI
Additional investigation is needed
positive
negative
Chest imaging
negative
positive
negative
positive
PET or TC/PET
Therapy
Close F/U
positive
negative
Follow-up procedures: CTF proposal
Close F/U or immediate therapy