neoadjuvant followed by interval cytoreduction francesco fanfani gynecologic oncology dpt....
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Neoadjuvant followed by interval cytoreduction
Francesco FanfaniGynecologic Oncology Dpt. Obstetrics & GynecologyCatholic University - [email protected]
Role of surgery in the natural history of AOC
Primary surgery
IDS
Secondary cytoreduction
Palliation
Role of the specialist in GYO1. Time of surgery2. Surgical skills and training3. Data collection4. Approved trial and International
Society5. Biological Background
Role of the specialist in GYO1. Time of surgery2. Surgical skills and training3. Data collection4. Approved trial and International
Society5. Biological Background
Decision making and judgement• What to do• When to do it• Why to do it• How to do it
Decision making and judgement• What to do• When to do it• Why to do it• How to do it
II look
WhyWhy should we select AOC patients for NACT instead of PDS ?
PDSPDS
Less extensive surgery; easier optimal cytoreduction; tumor biology is more important than RT; good experience in good experience in
other solid tumors other solid tumors
Less extensive surgery; easier optimal cytoreduction; tumor biology is more important than RT; good experience in good experience in
other solid tumors other solid tumors
NACTNACT
Several prospective data but no RCTs; prognostic value of RT; removal of chemo-resistant clones
Several prospective data but no RCTs; prognostic value of RT; removal of chemo-resistant clones Lack of data on QoL
lower complication ratesLack of data on QoLlower complication rates
Choosing the best treatment approach Choosing the best treatment approach in Advanced Ovarian Cancerin Advanced Ovarian Cancer
Potential advantages of PDS
Role of NACT
UCSC experience
Future perspectives
Hoskins , 1994
Bristow , 2002
Each Each 10% 10% increase of increase of optimal cytoreduction optimal cytoreduction raterateproduces aproduces a 5.5% 5.5% increase in median increase in median survivalsurvival
Survival effect of maximal cytoreductive surgery for Survival effect of maximal cytoreductive surgery for advanced OC during the platinum eraadvanced OC during the platinum era
Gynecologic oncology, 2010
RT = 0 (44%)
Median PFS = 19.9 months
“… all patients with no residual tumor had the best prognosis and in view of these results we believe that the gold standard of primary surgery should be considered as leaving no macroscopic tumor”
SITE Essen criteria Leuven criteria
Abdominal metastases
Multiple parenchymatous liver metastases Infiltration of large parts of the pancreas (not only tail) and/or the duodenumInfiltration of the porta hepatis or truncus coeliacusDeep infiltration of the radix mesenteriiDiffuse and confluent carcinomatosis of the stomach and/or small bowelInvolvement of the SMA
Intraephatic metastases Infiltration of the duodenum and/or pancreas and/or the large vessels of the porta hepatis or truncus coeliacus
Extra-abdominal metastases
Not completely resectable metastases All, excluding: resectable inguinal lymph nodes, solitary retrocrual or paracardial nodes, Pleural fluid cytologically malignant cells without presence of pleural tumors
Pts characteristics Poor PS-ECOG
(Vergote I and Du Bois A, 2012)
Criteria for NACT in FIGO stage IIIC-IV OC
Choosing the best treatment approach Choosing the best treatment approach in Advanced Ovarian Cancerin Advanced Ovarian Cancer
Potential advantages of PDS
Role of NACT
UCSC experience
Future perspectives
RANDOMISED EORTC-GCG/NCIC-CTG TRIAL ON NACT + IDS VERSUS PCS
No residuals per country (PP analysis)
Primary-OP(n = 310)
NACT -> IDS(n = 322)
Difference(%)
Belgium 63% 87% 24
Argentina (n=48) Excluded in NEJM
Sweden (n=23) Not shown in NEJM
The Netherlands 4 % 28 % 24
Italy 6 % 39 % 33
Norway 8 % 50 % 42
Spain 10 % 42% 32
UK 10 % 43% 33
Canada 11% 41 % 30
No residual after surgery 19.4 % 51.2 % 31.8%
Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS = 0 cm residual per country
Vergote et al., NEJM, 2010Vergote et al., NEJM, 2010
Median OS 29 mo.Median OS 29 mo.
Median PFS 12 mo.Median PFS 12 mo.
30 mo. 30 mo. 12 mo. 12 mo. NACT NACT PDS PDS n.s.n.s.
Compared with data retrieved from other prospective clinical trials in AOC and from retrospective series the OS and PFS reported by Vergote et al. seems to be too low
Choosing the best treatment approach Choosing the best treatment approach in Advanced Ovarian Cancerin Advanced Ovarian Cancer
Potential advantages of PDS
Role of NACT
UCSC experience
Future perspectives
Ovarian cancer (1986-2010) Ovarian cancer (1986-2010) Catholic University of the Sacred Heart
N o
f pati
ents
0
50
100
150
200
250
300
350
400
450
1986-90 1991-95 1996-2000 2001-2005 2006-2010
YEARS
Total Number of OC patients: 1087Stage IIIC-IV disease: 778 pts
Early stage OC
Advanced OC
Distribution of Surgical procedures
Ovarian cancer (1986-2010) Ovarian cancer (1986-2010) Catholic University of the Sacred Heart
Surgery in AOC patients: 994 procedures
PDS
IDS
IDS (referred fromsatellite centres)
Secondary surgery
Secondarysurgery+HIPEC
45%45%
16%16%
21%21%
10%10%
8%8%
67%67%
33%33%
Median PFS at PDS- RT = 0cm: 29 mts- RT ≤ 1 cm: 14 mts- RT > 1 cm: 13 mts
Median PFS at PDS- RT = 0cm: 29 mts- RT ≤ 1 cm: 14 mts- RT > 1 cm: 13 mts
Median PFS at IDS- RT = 0cm: 15 mts- RT ≤ 1 cm: 14 mts- RT > 1 cm: 10 mts
Median PFS at IDS- RT = 0cm: 15 mts- RT ≤ 1 cm: 14 mts- RT > 1 cm: 10 mts
RT = 0 cmRT = 0 cm
RT > 1 cmRT > 1 cm
Role of surgical effort on PFS in Our experience
p-value <0.0001p-value <0.0001
Cytoreductive surgery in AOC
Institution (Authors, years)
Number of pts Number of pts RT=0 at PDS
UCSC(Scambia G, 2012)
300 (Jan 2005-Dec 2010)
97 (32%)
MSKCC (Chi DS, 2012)
285(Sep 1998-Dec 2006)
69 (24%)
IEO(Peiretti M, 2012)
259(Jan 2001-Dec 2008)
115 (44%)
EORTC (Vergote I, 2010)
310 in PDS arm(Sep 1998-Dec 2006)
61 (19%)
161 women who underwent laparotomy by OC completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of life questionnaires (QLQ C30 and ‐QLQ OV28) presurgery and at 1 month‐
161 women who underwent laparotomy by OC completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of life questionnaires (QLQ C30 and ‐QLQ OV28) presurgery and at 1 month‐
It was observed a significant impact on HRQOL among gynecologic cancer patients, 1 month after laparotomy, particularly among those
with Ovarian Cancer
It was observed a significant impact on HRQOL among gynecologic cancer patients, 1 month after laparotomy, particularly among those
with Ovarian Cancer
CLINICAL EVALUATION
Adequate planning of surgery
Assessment of extrabdominal disease
Prediction of optimal
cytoreductive surgery?
A step by step approach to AOC
CA125 levels Chi DS et al, 2009Chi DS et al, 2009
Combined score: Age, ASA score, Albumine levels, Tumor burden Aletti DG et al, 2011Aletti DG et al, 2011
CLINICAL EVALUATION alone can not be safely used to predict optimal
cytoreductive surgery
A step by step approach to AOC
CA125 levels Chi DS et al, 2009Chi DS et al, 2009
Combined score: Age, ASA score, Albumine levels, Tumor burden Aletti DG et al, 2011Aletti DG et al, 2011
CLINICAL EVALUATION alone can not be safely used to predict optimal
cytoreductive surgery
A step by step approach to AOC
CT scan+ECOG PS Ferrandina G et al, 2010Ferrandina G et al, 2010
Prediction of optimal cytoreduction: performance of CT and PS-ECOG
CT scan: PPV ranging from 59.5 to 82.1; NPV from 50.4 to 74.3 PS-ECOG: PPV 85.7; NPV 54.7
N=195
Combined score: Age, Tumor burden, ASA score, Albumine levels Aletti DG et al, 2011Aletti DG et al, 2011
CA125 levels
CT scan+ECOG PS Ferrandina G et al, 2010Ferrandina G et al, 2010
Ultrasound Testa AC et al, 2012Testa AC et al, 2012
Chi DS et al, 2009Chi DS et al, 2009
A step by step approach to AOC
CLINICAL EVALUATION and the prediction of optimal cytoreductive surgery
US score performance could be improved by instrumental/clinical data
US score is not prospectively validated
US score applicability is limited to other oncological centres
At 5 points of US scoreNPV=31.3%PPV=92%
At 5 points of US scoreNPV=31.3%PPV=92%
Ca125: 17 retrospective CT/MRI: 8 retrospective Clinico-pathological variables: 5 retrospective
A universally applicable clinical model that can predict which patients will undergo optimal cytoreduction remains elusive
A universally applicable clinical model that can predict which patients will undergo optimal cytoreduction remains elusive
Int J Gynecol Cancer 2010; 201: S1-11Int J Gynecol Cancer 2010; 201: S1-11
Is Clinical evaluation adequate to select AOC patients for NACT instead of PDS?
A review (1980-2009)A review (1980-2009)
Suspicious diagnosis of AOC
CLINICAL EVALUATION
Planning of surgery Assessment of
extrabdominal disease Prediction of the
outcome of cytoreductive surgery??
LAPAROSCOPY
A step by step approach to AOC
Proposal for a treatment algorithm
Rationale No definitive guidance or clinical recommendation for PCS vs.
NACT.
A variable percentage, from 10 to 80%, of AOC patients will undergo only explorative laparotomy.
Parameters associated with the possibility of cytoreduction can be easily assessable by LPS.
The surgeon may be more comfortable with a direct visualization of the cancer spread.
LPS could reduce some laparotomy-related complications and could be taken into consideration in women showing several risk factors for incisional hernia (Fagotti et al., AJOG 2011)
20052005
20062006 20082008
2010201020112011
20122012
S-LPS can subjectively assess OC (prospective evaluation)
Elaboration of an objective LPS-score (PIV) to assess OC (retrospective evaluation)
Evolution of S-LPS Evolution of S-LPS as a new diagnostic tool in AOCas a new diagnostic tool in AOC
Prospective validation of an objective LPS-score (PIV) to assess OC
Retrospective validation of an objective LPS-score (PIV) to assess OC in an external centre
Reproducibility of PIV for fellow in GYO
Prospective multicentric validation of PIV.
Reproducibility of PIV At IDS
Am J Obstet Gynecol. 2008
Predictive index parameter
Sensitivity(%)
Specificity(%)
PPV(%)
NPV(%)
Accuracy(%)
Point value
Ovarian masses Ovarian masses (mono-bilateral)(mono-bilateral)
6060 2929 2929 6060 3939 0
Omental cake Omental cake 5757 8181 6363 7777 7373 2
Peritoneal carcinosisPeritoneal carcinosis 6969 7979 6767 8181 7575 2
Diaphragmatic Diaphragmatic carcinosiscarcinosis
6969 8484 6565 8080 8080 2
Mesenteral retractionMesenteral retraction 5050 9595 8585 7777 7878 2
Bowel infiltrationBowel infiltration 7070 8989 7878 8484 8282 2
Stomach infiltrationStomach infiltration 1111 100100 100100 8282 8282 2
Liver metastasesLiver metastases 3535 9494 7575 7676 7676 2
Am J Obstet Gynecol. 2008
OVERALL LAPAROSCOPIC PREDICTIVE MODEL (PIV) ACCORDING TO DIFFERENT CUT-OFF VALUES
PIVPIV NPV (%)NPV (%)Unnecessarily Unnecessarily
explored explored (1 – NPV) (%)(1 – NPV) (%)
PPV (%)PPV (%) Inappropriately unexploredInappropriately unexplored(1 – PPV) (%)(1 – PPV) (%)
00 89.489.4 10.610.6 58.558.5 41.541.5
22 84.384.3 15.715.7 64.264.2 35.835.8
44 80.880.8 19.219.2 72.772.7 27.327.3
66 71.271.2 28.828.8 9090 1010
88 59.559.5 40.540.5 100100 00
1010 51.451.4 48.648.6 100100 00
p = ns
2011
The laparoscopic assessment of peritoneal cancer diffusion according PIV can be carried out by a fellow in GYO after 12 months’ experience
The laparoscopic assessment of peritoneal cancer diffusion according PIV can be carried out by a fellow in GYO after 12 months’ experience
Algorithm of AOC patients at the UCSC(Rome-Campobasso)
S-LPS
PIV>8PIV<8
OPTIMAL CYTOREDUCTION
NACT(3-4 cycles)
RECIST/GCICcriteria
PROGRESSION STABLE/PARTIALRESPONSE
COMPLETE RESPONSE
IDSII-line CT IDS
AOCAOC
Institution (Authors, years)
Number of pts Median PFS (months)
Median OS (months)
UCSC(Scambia G, 2012)
207 (Jan 2005-Dec 2010)
16 45
MSKCC (Chi DS, 2012)
285(Sep 1998-Dec 2006)
17 50
IEO(Peiretti M, 2012)
259(Jan 2001-Dec 2008)
20 57
EORTC (Vergote I, 2010)
310 in PDS arm(Sep 1998-Dec 2006)
12 30
Introducing S-LPS in the management of advanced epithelial ovarian, tubal, peritoneal cancer:
impact on prognosis in a single institutional series
Chi DS et al, Gynecologic Oncology 2012Chi DS et al, Gynecologic Oncology 2012
The MSKCC Model
Jan 2005-Dec 2010 300 Epithelial AOC pts§
Poor ECOG-PS59 pts (20%)
Eligible 207 pts (69%)
The UCSC Model
Clinically unresectable34 pts (11%)
Optimal cytoreduction
7 pts (21%)
LPS
Optimal cytoreduction12 pts (19%)
NACT 47 pts
(81%)
NACT 27 pts
(79%)
Suboptimal cytoreduction
15 pts (7%)
NACT 78 pts
(38%)
Optimal cytoreduction114 pts (55%)
The UCSC Model
LPS allows to:
Recruit 20% of pts with poor PS-ECOG or clinically unresectable disease for optimal PDS
Avoid unnecessary LPT in around 64.1% of AOC pts selected for NACT
Choosing the best treatment approach Choosing the best treatment approach in Advanced Ovarian Cancerin Advanced Ovarian Cancer
Potential advantages of PDS
Role of NACT
UCSC experience
Future perspectives
FUTURE PERSPECTIVES
In the grey zone of OC pts with 8≤PIV≤12, can we safely avoid PDS?
Pre-op assessed for eligibility
Excluded-Not meeting inclusion criteria (poor PS, older than 80, stage IV pulmonary, LPN, multiple hepatic)- Refused to participate
Randomized Randomized
Maximal surgical effort NACT + IDS
Enro
llmen
tEn
rollm
ent
SCORPION (NCT01461850) SCORPION (NCT01461850) Surgical Complications Related to Primary vs. IDS Surgical Complications Related to Primary vs. IDS
in Ovarian Neoplasmsin Ovarian Neoplasms
SCORPION (NCT01461850) SCORPION (NCT01461850) Surgical Complications Related to Primary vs. IDS Surgical Complications Related to Primary vs. IDS
in Ovarian Neoplasmsin Ovarian NeoplasmsAl
loca
tionAl
loca
tion
F UF UAn
alys
isAnal
ysis
8 < PI < 12
Starting date October 26, 2011 RecruitingStarting date October 26, 2011 Recruiting
Conclusions
We confirm that patients with no residual tumor at PDS have the best prognosis
Delaying surgery after NACT seems a reasonable option when a right selection of patients is performed
More in depth evaluations are required to clarify the impact of NACT on the natural history of AOC
To resolve the controversies …..
compare opinions and….share data?