Neoadjuvant followed by interval cytoreduction Francesco Fanfani Gynecologic Oncology Dpt. Obstetrics & Gynecology Catholic University - Rome [email protected]

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



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



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

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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


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


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


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


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



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?

Documents

Neoadjuvant followed by interval cytoreduction Francesco Fanfani Gynecologic Oncology Dpt. Obstetrics & Gynecology Catholic University - Rome [email protected]