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Ahmed Sekotory M. Ahmed MD FRCOG FACOG

Consultant Gynaecologist & Gynaecological Oncologist

Hon Prof Gynae-Oncology. The National Cancer Institute; Cairo; Egypt

Advanced Ovarian Cancer

Upfront Surgery Vs Neo-Adjuvant Chemotherapy

4th EGOS & 8th GO Meeting; 12th December 2024; Cairo

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

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Contents

Introduction & Epidemiology
Upfront Surgery
Neo-Adjuvant Chemo
HIPEC
Other updates
Summary & Recommendations

No Undisclosed Interests

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Introduction & Epidemiology

ADVANCED OVARIAN CANCER

UPFRONT SURGERY Vs NEO-ADJUVANT CHEMOTHERAPY

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Most frequent cancers in Egypt 2008 - 2011

Ibrahim et al 2014

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Ovarian cancer in Egypt

The annual incidence of ovarian cancer in Egypt:�5.4 / 100,000 women
The rate in women < 50 years is 2.5 / 100,000 women
The rate in women > 50 years is 14.9 / 100,000 women
The rate in women 50-69 years is 17.7 / 100,000 women

Ibrahim et al 2014

The proportion of women younger than 50 years with ovarian cancer in Egypt is approximately 45%!

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Ovarian Cancer: projected annual case load (Egypt)

Ibrahim et al 2014

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80%: present in advanced stage

80%: respond to surgery & chemo

80%: relapse within 2 years

80%: of them will die within further 2 years

Ovarian Cancer

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Progress in ovarian cancer Siegel et al 2014

Goff B GO 2015

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EOC: Progress In WHO Classification!

Martin Köbel & Eun Young Kang 2022

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EOC: Frequent histo-types

Epithelial Ovarian Cancer (EOC) > 90 % of Ovarian Cancer
High Grade Serous Ovarian Carcinoma (HGSOC)	Low Grade Serous Ovarian Carcinoma (LGSOC)	Mucinous Ovarian Carcinoma (MOC)	Endometrioid Ovarian Carcinoma (EnOC)	Clear Cell Ovarian Carcinoma (CCC)
70%	5%	3%	10%	10%

Part J et al 2018; cited by Ciucci et al 2022

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Molecular Classification in EOC; WHY?

Does one-size-fit-all?!

Epidemiologic & Genetic Risk Factors
Precursor Lesions
Patterns of Spread
Molecular Events During Oncogenesis
Response to Chemotherapy
Prognosis Part J et al 2018; cited by Ciucci et al 2022

“Awareness is the greatest agent for change” Eckhart Tolle

More Insight

Personalised Treatment

Improved outcome

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High Grade Serous Ovarian Carcinoma (HGSOC)

70% of Epithelial Ovarian Cancer
Usually presents in an advanced stage
Initial good response to standard chemotherapy
Majority will relapse
Eventually will develop drug resistance
5 Year Survival is generally poor (approx. 40%)

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EOC: Dualistic classification & Molecular input

Dion Et Al 2020

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Alba Mota et al 2018

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Upfront Surgery

ADVANCED OVARIAN CANCER

UPFRONT SURGERY Vs NEO-ADJUVANT CHEMOTHERAPY

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Primary cytoreductive surgery: “staging laparotomy”

Griffiths

1975

Residual disease < 1.5 cm is associated with survival advantage

Hoskins

1992 & 1994

Residual Disease:

Nil: 60% 5y Sur

<2cm: 35% 5y Sur

>2cm: 20% 5y Sur

Eisenkop

1998

Complete Cytoreduction (via radical surgery) is feasible and safe in most patients

Surgical Outcome: according to residual disease (RD)

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Primary cytoreductive surgery: “staging laparotomy”

Surgical Outcome

(according to residual disease)

Complete Cytoreduction

No Residual Disease

Optimal Cytoreduction

Residual disease < 1 cm

GOG Definition

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CRS in Ovarian Cancer

Surgery may involve:

Removal of the uterus, tubes and ovaries
Retroperitoneal Lymph Node Dissection
Removal of the right hemicolon, spleen, gall bladder, greater and lesser omentum, and parts of the stomach
Stripping of the peritoneum from the pelvis and diaphragm
Stripping of tumour from the surface of the liver
Removal of the rectum in some cases.

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Radical Primary surgery:�to achieve complete/optimal cytoreduction

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Radical primary cytoreductive surgery

Residual disease	Survival (months)
No residual disease	106
≤ 0.5 cm	66
0.6 – 1 cm	48
1 - 2 cm	33
> 2 cm	34

Chi et al 2006

Dennis Chi

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Radical primary cytoreductive surgery

Residual disease 3126 pt	Survival (months)
No residual disease	99
≤ 1 cm	36
> 2 cm	29

Du Bois et al 2009

Du Bois

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CRS for Advanced Ovarian Cancer

Resection of diaphragmatic recurrence

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CRS for Advanced Ovarian Cancer

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CRS for Advanced Ovarian Cancer

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Lymphadenectomy in advanced Ovarian Cancer

ADVANCED OVARIAN CANCER

UPFRONT SURGERY Vs NEO-ADJUVANT CHEMOTHERAPY

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The role of lymphadenectomy in advanced ovarian cancer

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Harter et al. NEJM 2019

The role of lymphadenectomy in advanced ovarian cancer

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A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms. Harter et al NEJM 2019

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A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms. Harter et al NEJM 2019

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A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms. Harter et al NEJM 2019

CONCLUSIONS

Systematic pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer who had undergone intraabdominal macroscopically complete resection and had normal lymph nodes both before and during surgery was not associated with longer overall or progression-free survival than no lymphadenectomy and was associated with a higher incidence of postoperative complications.

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Heated Intraperitoneal Chemotherapy (HIPEC)

ADVANCED OVARIAN CANCER

UPFRONT SURGERY Vs NEO-ADJUVANT CHEMOTHERAPY

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Peritoneal Carcinomatosis Index (PCI)

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HIPEC Technique:

Intraperitoneal Chemotherapy Heated 40-43 degrees
Perfusion from 60 – 120 minutes before draining
Closure with Intraperitoneal drains

Further post-operative courses of intravenous or intraperitoneal chemotherapy may be given

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Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

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CRS & HIPEC in Ovarian Cancer

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HIPEC in Ovarian Cancer

Important issues

Timing of the procedure
Which chemotherapy
Temperature to be used
Duration of HIPEC perfusion

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The addition of HIPEC to CRS and chemotherapy improves overall survival rates for both primary and recurrent EOC

Huo YR et al 2016

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HIPEC in Ovarian Cancer Huo et al 2015

Systematic Review and Meta-analysis:

9 Comparative Studies
28 Studies of CRS & HIPEC
Primary and Recurrent disease were included

Conclusion:

The addition of HIPEC to CRS and Chemotherapy has overall survival advantage in patients with FIGO III and recurrent EOC

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HIPEC in Recurrent Ovarian Cancer: Spiliotis et al 2015

	CRS + HIPEC + IV Chemo	CRS + IV Chemo
PT number	60	60
Mean Survival (months)	27	13
Mean Survival in Platin Sensitive (months)	26.8	15.2
Mean Survival in Platin Resistant (months)	26.6	10.2
3-Year Syrvival	75%	18%

Conclusion

The use of HIPEC plays an important role in the survival of patients with recurrent ovarian cancer irrespective of “Platin sensitivity”

Spiliotis et al 2015

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

Spiliotis et al. (2015) evaluated the use of HIPEC for treating recurrent epithelial ovarian cancer. In an 8-year period

(2006-2013), 120 women with advanced ovarian cancer who experienced disease recurrence after initial treatment

with conservative or debulking surgery and systemic chemotherapy were randomized into two groups. Group A was

comprised of 60 patients treated with CRS followed by HIPEC and then systemic chemotherapy. Group B was

comprised of 60 patients treated with CRS only and systemic chemotherapy. The mean survival for group A was 26.7

versus 13.4 months in group B. Three-year survival was 75% for group A versus 18% for group B. In the HIPEC group,

the mean survival was not different between patients with platinum-resistant disease versus platinum-sensitive

disease (26.6 vs. 26.8 months). In the non-HIPEC group, there was a statistically significant difference between

platinum-sensitive versus platinum-resistant disease (15.2 vs. 10.2 months). The authors concluded that the use of

HIPEC, extent of disease and extent of cytoreduction play an important role in the survival of patients with recurrence

in an initially advanced ovarian cancer. While these results are promising, additional randomized controlled trials are

needed to conclude that HIPEC + CRS + chemotherapy is superior to CRS + chemotherapy alone for ovarian cancer

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CRS & HIPEC in Ovarian Cancer: Cumulative Survival Rate Munoz-Casares FC et al 2016

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CRS & HIPEC in Ovarian Cancer: Cumulative Survival Rate Munoz-Casares FC et al 2016

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

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CRS & HIPEC in Ovarian Cancer: Cumulative Survival Rate Munoz-Casares FC et al 2016

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CRS & HIPEC in Ovarian Cancer: Cumulative Survival Rate Munoz-Casares FC et al 2016

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Conclusion

Cytoreductive surgery and HIPEC seem to be associated with promising results in patients with recurrent ovarian cancer

DFS: 8.5 – 48 months

Hotouras A et al 2016

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Conclusion

Favorable 5 and 7-year Post-Relapse Survival (PRS) rates for platinum-sensitive REOC patients undergoing CRS & HIPEC (52.8 and 44.7 % respectively). No mortality. Grade 3-4 Morbidity: 8.6%.

Median Post-Relapse Survival: 63 months

Hotouras A et al 2016

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Residual disease more than 2.5 mm and positive lymph node status are associated with early recurrence (within 1 year) after CRS and HIPEC for recurrent ovarian cancer. (Level-III)

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HIPEC in Ovarian Cancer

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HIPEC in Ovarian Cancer

Gynecologic Cancer J 2017: Randomized trial of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with primary advanced peritoneal, ovarian, and tubal cancer. Myong Cheol Lim, Suk-Joon Chang, Heong Jong Yoo, Byung-Ho Nam, Robert Bristow, Sang-Yoon Park Show More
184 pts (HIPEC, 92; control, 92):

No mortality was identified and postoperative morbidities were not statistically different between two groups except anemia and creatinine elevation in HIPEC group. The survival analysis did not show the statistical superiority of the HIPEC arm

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HIPEC in Ovarian Cancer:

Harter et al 2016

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CRS & HIPEC in Ovarian Cancer (RCT)

W.J. van Driel et al 2018

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CRS & HIPEC in Ovarian Cancer: Pt. Characteristics

W.J. van Driel et al 2018

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CRS & HIPEC in Ovarian Cancer: Pt. Characteristics

W.J. van Driel et al 2018

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CRS & HIPEC in Ovarian Cancer (RCT): Survival

W.J. van Driel et al 2018

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CRS & HIPEC in Ovarian Cancer: Recurrence Free Survival W.J. van Driel et al 2018

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CRS & HIPEC in Ovarian Cancer: G 3-4 Adverse Events W.J. van Driel et al 2018

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CRS & HIPEC in Ovarian Cancer (RCT): Summary

W.J. van Driel et al 2018

	SURGERY	SURGERY + HIPEC	HR
Recurrence or Death at end of FU period	110/123 (89%)	99/122 (81%)	0.66
Median Recurr. Free Survival (m)	10.7	14.2
Mortality at 4.7 Years (median FU)	62%	50%	0.67
Median Overall Survival (m)	33.9	45.7
G 3-4 Adverse Events	25%	27%	NS

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CRS & HIPEC in Ovarian Cancer (RCT): Conclusion

W.J. van Driel et al 2018

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CRS & HIPEC: Quality of Life

Physical functioning (mean score improved from 69.5 to 80 at 6 months)
Problems with daily activities as a result of physical functioning (mean score improved from 36.3 to 53 at 1 year; p = 0.016)
Bodily pain (mean score improved from 64.8 to 81.5 at 1 year; p = 0.0007)

McQuellon RP et al 2007

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CRS & HIPEC: Postoperative Mortality

Study	Type	Mortality
Verwaal VJ et al 2008	RCT of 105 patients	7.4%
Glehen O et al 2004	Non-randomised comparative study of 506 patients	4% (Digestive fistula caused 1/3 of deaths)
Shen P et al 2008	Non-randomised comparative study of 222 patients	5.5% (no difference in both groups)
Levine EA et al 2007	Case series of 460 patients	4.8%

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CRS & HIPEC: Postoperative Morbidity

Morbidity		Study
Return to Theatre/ITU	5–36%	Bijelic L et al 2007 Systematic review of 291 patients
Bowel perforation / Leak rate	2.5 – 12%	Bijelic L et al 2007 Systematic review of 291 patients
GE Fistula	3.5 – 15%	Bijelic L et al 2007 Systematic review of 291 patients
GE Fistula	14.6%	Verwaal VJ et al 2008 RCT of 105 patients
GE Fistula	8.3%	Glehen O et al 2004 Non-randomised comparative studies of 506

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CRS & HIPEC: Postoperative Morbidity

Morbidity		Study
Sepsis	5 – 8 %	Bijelic L et al 2007 Systematic review of 291 patients
Sepsis	2%	Glehen O et al 2004 Non-randomised comparative studies of 506
Pancreatitis	2.1%	Verwaal VJ et al 2008 RCT of 105 patients
Acute Renal Failure	0.7 – 3.4 %	Case Series x 2 (140 pt & 59 pt) Yan TD et al 2007 Roviello F et al 2014
Cardio-Respiratory*	2 – 10 %	NICE Literature Rev 2009

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CRS & HIPEC: Postoperative Morbidity

Morbidity		Study
Haematological Toxicity	0 – 15 %	NICE Literature Rev 2009 Bijelic L et al 2007 Systematic review of 291 patients
Thromboembolic	0.4 – 5.8 %	NICE Literature Rev 2009 Bijelic L et al 2007: Systematic review of 291 patients Glehen O et al 2004: Non-randomised comparative studies of 506
Neurological	1.2%	Muller H et al 2008 Case series of 241 patients
Re-Operation Rate	0 – 16 %	NICE Literature Rev 2009 Bijelic L et al 2007: Systematic review of 291 patients Glehen O et al 2004: Non-randomised comparative studies of 506

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Safety of extraperitoneal rectal resection and ileo- or colorectal anastomosis without loop ileostomy in patients with peritoneal metastases treated with CRS and HIPEC Andreas Brandl et al 2018
Patients with bowel anastomosis (n)	53
Mean Age	57 years
PCI Index (Mean)	24
Complete Cytoreduction	33 (62%)
Permanent ileostomy/colostomy	5 (9%)
Prophylactic ileostomy	1 (2%)
Anastomotic Leak	1/47 (2%)
Surgical Complications	21 (40%)
Medical Complications	41 (77%)
Mortality	7.5%

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Protective stoma should be considered in extensive CRS–HIPEC procedures requiring two or more bowel anastomoses in order to reduce the postoperative morbidity rate. Jacoby et al 2018

Anastomotic Leak 6% Vs 37%

Reoperation 0 Vs 28%

Overall Morbidity 6% Vs 41%

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Conclusion: Cytoreductive surgery and HIPEC for peritoneal carcinomatosis may be safely performed with acceptable morbidity in selected elderly patients

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CRS & HIPEC in Ovarian Cancer: G 3-4 Adverse Events W.J. van Driel et al 2018

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CRS & HIPEC: Service Delivery Considerations

Quality Management System

Centre allocation.

Team building, Training & Development

Data Information System & Research Governance

SOP & Protocols:

- Clinical Standards

- Service Standards

Regular Audits:

- Auditable Measures

- Key Performance Indicators

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Neo-Adjuvant Chemotherapy

ADVANCED OVARIAN CANCER

UPFRONT SURGERY Vs NEO-ADJUVANT CHEMOTHERAPY

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???

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???

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Neo adjuvant chemotherapy Delayed primary debulking surgery

Nature 467, 543–549 (30 September 2010)

Neo adjuvant chemotherapy & Delayed Primary Debulking surgery offer an alternative to upfront surgery in a selected group with comparable survival at less morbidity… CHORUS & EORTC Trials 2015

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ESGO Guidelines on Management of EOC

ESMO-ESGO Consensus Conference on Ovarian Cancer

Pathology and molecular biology, early and advanced stages, borderline ovarian tumours and recurrent disease

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Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

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Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

86 of 97

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

87 of 97

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

88 of 97

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

89 of 97

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

90 of 97

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

91 of 97

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

92 of 97

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

93 of 97

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

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Summary & Recommendations

ADVANCED OVARIAN CANCER

UPFRONT SURGERY Vs NEO-ADJUVANT CHEMOTHERAPY

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

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Summary & Recommendations

Advanced ovarian cancer remains a challenge and efforts should concentrate on early detection
Treatment should be by designated teams in suitable centers.
Management should be within Clinical Research Portfolio.
Service delivery standards, robust data collection and regular monitoring should be implemented

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

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Summary & Recommendations

CRS outcome and residual disease are, so far, the most important prognostic indicators
Maximum efforts at complete/optimal primary cytoreduction in suitable patients is the way forward, otherwise neoadjuvant chemo.
The establishing role for CRS & HIPEC in Advanced Epithelial Ovarian Cancer needs continuous appraisal
Inoperable, unfit patients and those with low probability of complete/optimum CRS should go for NAC

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024

97 of 97

ADVANCED OVARIAN CANCER:

CRS vs NAC

Ahmed Sekotory M. Ahmed MD FRCOG FACO

ahmedsekotory@hotmail.com

Advanced Ovarian Cancer: Upfront CRS vs NAC. Ahmed Sekotory M Ahmed MD FRCOG FACOG. 4EGOS-8GO Conf; 12 Dec 2024