1. Surgery for Ovarian Cancer: Progress and Future Directions
Michael J. Worley Jr. MD
Division of Gynecologic Oncology
Brigham and Women’s Hospital
Dana Farber Cancer Institute
Assistant Professor
Harvard Medical School

2. Conflict of Interest Disclosure
I have no financial relationships with a commercial entity producing healthcare-related products and/or services.

3. Thank You

4. Role of Surgery for Ovarian Cancer
Initial Diagnosis
Establish diagnosis
Establish stage and extent of disease
Improving survival
Recurrent Disease
Relief of symptoms

5. Most Patients Present with Advanced Disease
>70% of patients present with stage III-IV disease
Lymph nodes
Abdominal cavity
Peritoneal surfaces
Abdominal organs
Distant
Malignant fluid within the lungs

6. Prognostic Factors Age Performance-status FIGO stage Histology
Type of chemotherapy
Residual disease at the completion of surgery

7. Initial Surgical Approaches

8. Primary Debulking Surgery
Neoadjuvant Chemotherapy

9. Objectives What is new in surgery Review of recent surgical trials
How have we expanded our knowledge?
Where have we improved?
Review of recent surgical trials
LION trial
DESKTOP trial

10. There it is!!!

11. Now, remove it!!!

13. Aggressive Surgery and Survival
Residual disease at the completion of surgery
Preoperative disease burden
Just the abdomen and pelvis?
Disease in the lymph nodes?
Disease in the upper abdomen?
SURVIVAL
RESIDUAL DISEASE
PREOP DISEASE BURDEN

14. It doesn’t matter what the patient enters the operating room with
It doesn’t matter what the patient enters the operating room with. It matters what they leave the operating room with.

15. Considering Both Factors…
Longest survival 
Enter the OR with low/moderate volume disease and
Leave the OR with the lowest volume of disease (i.e. complete resection)
Surgical resection and initial disease burden strongly influence survival
Surgical resection alone doesn’t overcome initial disease burden
Horowitz NS, et al. Does aggressive surgery improve outcomes? Interaction between preoperative disease burden and complex surgery in patients with advanced-stage ovarian cancer: an analysis of GOG 182. J Clin Oncol Mar 10;33(8):
Horowitz NS, et al. Does aggressive surgery improve outcomes? Interaction between preoperative disease burden and complex surgery in patients with advanced-stage ovarian cancer: an analysis of GOG 182. J Clin Oncol Mar 10;33(8):

16. Goal of Debulking Surgery
“Optimal”: no residual tumor nodule >1 cm at the end of surgery
Longest survival is seen after complete resection of disease (R0) R0
Optimal

17. This is complete resection (R0)

18. This is “optimal”

19. This is “optimal”

20. ≠

21. Are all “optimal” patients the same?

22. Complete resection (R0)
Optimal with single site residual (<1cm-SL)
Suboptimal resection (>1cm residual)
Optimal with multi-site residual (<1cm-ML)

23. Volume of Residual Disease and Survival
Longest survival associated with R0 resection
Patients with a single site of residual disease have a similar survival to R0
Some differences based on primary debulking surgery and neoadjuvant chemotherapy
Patients with multi-site residual disease have a similar survival

24. Complete resection (R0)
Optimal with single site residual (<1cm-SL)
Suboptimal resection (>1cm residual)
Optimal with multi-site residual (<1cm-ML)

25. Complete resection (R0)
Optimal with single site residual (<1cm-SL)
Suboptimal resection (>1cm residual)
Optimal with multi-site residual (<1cm-ML)

26. Complete resection (R0)
Optimal with single site residual (<1cm-SL)
Suboptimal resection (>1cm residual)
Optimal with multi-site residual (<1cm-ML)

27. Who has had a similar experience?

28. Don’t eat anything until you pass gas.

29. You will have IV fluids for the next few days.

30. We can give you narcotics for pain control.

31. Management of the Surgical Patient
Traditional Management
- Little to no supporting evidence for practices
- Taught, practiced and passed along
- Highly variable care
Evidence-Based Management
- Best practices are based on data
- Consistent guidelines
- Limit variability to minimize mistakes and improve quality

32. Enhanced Recovery After Surgery (ERAS®)
Don’t starve patients prior to surgery
Allow patients to eat and drink after surgery
Limit postoperative IV fluids
Use multiple ways to control postoperative pain
Get patients out of bed

33. How many runners had nothing to eat or drink after midnight?

34. Preoperative Carbohydrate Treatment
Intake of clear liquids until 2 hrs. prior to surgery is safe
Reduces stress response with surgery
Reduces nausea and vomiting
Improves healing and wellbeing
Nelson G, et al. Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations--Part I. Gynecol Oncol Feb;140(2):
Nelson G, et al. Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations--Part I. Gynecol Oncol Feb;140(2):

35. Postoperative Oral Intake
Accelerates return of bowel function
Reduces length of stay
Improves patient satisfaction
A regular diet within 24 hrs. after surgery is recommended
Nelson G, et al. Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations--Part II. Gynecol Oncol Feb;140(2):
Nelson G, et al. Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations--Part II. Gynecol Oncol Feb;140(2):

36. Postoperative Fluid Therapy
Postoperative IV fluids beyond hrs. is rarely needed in an uncomplicated recovery
Oral intake of fluid and food should be started the day of surgery
Nelson G, et al. Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations--Part II. Gynecol Oncol Feb;140(2):

37. Postoperative Pain Control
Multimodal pain control
NSAIDs, acetaminophen
Reduces pain
Reduces opioid consumption
Improves patient satisfaction
Thoracic epidural pain control
Decreases stress response
Decreases postoperative pain and opioid consumption
Reduces time to bowel recovery
Nelson G, et al. Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations--Part II. Gynecol Oncol Feb;140(2):

38. Earl Mobilization Reduces postoperative complications
Pulmonary
Muscle atrophy
Blood clots
Reduces hospital length of stay
Barriers to early mobilizations
Foley catheters
Poor pain control
IV poles
Nelson G, et al. Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations--Part II. Gynecol Oncol Feb;140(2):

39. Cancer Related Benefits to ERAS®
Improves survival for other cancers
Colorectal cancer: Decreases 5-year risk of dying from cancer by 42%
Studies for ovarian cancer are ongoing
Epidural use associated with decreased risk of recurrence
Gustafsson UO, Adherence to the ERAS protocol is Associated with 5-Year Survival After Colorectal Cancer Surgery: A Retrospective Cohort Study. World J Surg Jul;40(7):
Elias KM. Anesthetic selection and disease-free survival following optimal primary cytoreductive surgery for stage III epithelial ovarian cancer. Ann Surg Oncol Apr;22(4):
Gustafsson UO, Adherence to the ERAS protocol is Associated with 5-Year Survival After Colorectal Cancer Surgery: A Retrospective Cohort Study. World J Surg Jul;40(7):
Elias KM. Anesthetic selection and disease-free survival following optimal primary cytoreductive surgery for stage III epithelial ovarian cancer. Ann Surg Oncol Apr;22(4):

40. Results From Recent Surgical Trials

41. Para-aortic Lymph Node Dissection During Debulking Surgery
Abdominal disease  removal of gross disease
Evaluation of para-aortic region
Even if nodes are not enlarged
Improves survival???

42. Lymphadenectomy in Ovarian Neoplasm (LION)
Eligible patients
FIGO stage IIB-IV ovarian cancer
No bulky lymph nodes
Complete resection of disease
No lymph node dissection
Lymph node dissection
Primary End Point
Overall survival
Secondary End Points
Progression free survival
Quality of life
Primary Outcome Measures: Overall Survival [ Time Frame: time from randomization until death ]
Secondary Outcome Measures: - Progression-free survival (PFS) - Quality of life (QoL) as measured by EORTC QLQ-C30, OV28 - number of resected lymph nodes [ Time Frame: Progression-free survival time is calculated from the date of surgery until the date of first progressive disease or death, whichever occurs first or date of last contact (censored observation). ]

43. LION Study Results
No difference in progression-free or overall survival
Lymphadenectomy associated with:
Longer surgeries
Greater blood loss
Higher rates of blood transfusions
Serious postoperative complications
Reoperation
Readmission
Death within 60 days of surgery
Surgery in the LNE arm was 64 minutes longer (means: 352 vs 288 min), resulted in a higher median blood loss (650 vs 500 ml), and a higher transfusion rate (67% vs 59%). Furthermore, serious post-operative complications occurred more frequently in the LNE arm (e.g. rate of re-laparotomies 12.1% vs 5.9% [p=0.006], hospital re-admittance rate 8.0% vs 3.1% [p=0.006] and deaths within 60 days after surgery 3.1 vs 0.9% [p=0.049]). Conclusions: Systematic pelvic and para-aortic LNE in patients with AOC with both intra-abdominal complete resection and clinically negative LN neither improve overall nor progression-free survival despite detecting (and removing) sub-clinical retroperitoneal lymph node metastases in 56% of the patients. Our data indicate that systematic LNE of clinical negative LN in patients with AOC and complete resection should be omitted to reduce post-operative morbidity and mortality. Clinical trial information: NCT

44. Surgery for Recurrent Ovarian Cancer
Most gynecologic oncologists agree that surgery for recurrent disease is beneficial
No high-quality evidence to define the role of secondary debulking surgery
Patient selection
Goals of surgery (i.e. how much residual disease)
Factors associated with success

45. Debulking surgery then chemotherapy
DESKTOP III Study
Eligible patients
1st recurrence
PFS ≥ 6 months
Positive AGO score:
Good performance status (PS=0)
R0 at initial surgery
<500 mL of ascites
R0 possible
Chemotherapy alone
Debulking surgery then chemotherapy
Primary End Point
Overall survival
Secondary End Points
Progression free survival
Quality of life

46. DESKTOP III Study Results
Overall survival results are not yet available
Complete resection achieved in 67% of patients
Surgery improved progression-free survival by 5 months
Greatest benefit for patients with R0 resection
No excessive toxicity or treatment burden
The time to third-line therapy was prolonged by a highly statistically significant median of 7.1 month (hazard ratio, 0.6). “What was the trade-off for these benefits? The patients did not pay for it with excessive mortality,” he said, explaining that no significant differences were seen between the groups in terms of mortality at 30, 60, 90, or 180 days, and that no excessive toxicity or treatment burden was seen in either group.
Dr. Ritu Salani
Median age of the patients was 60 years; they were enrolled at 80 centers in 12 countries between 2010 and The platin-free interval exceeded 12 months in 75% and 76% of patient in the surgery and control arms, respectively. Chemotherapy regimens in both the treatment and control arms were selected according to institutional standards, although platinum-based combination therapy was strongly recommended; 87% and 88% in the groups, respectively, received a platinum-containing second-line therapy. Macroscopic complete resection was achieved in 72.5% of patients in the surgery arm, which was the rate predicted by the AGO scores. “We know that the surgery and chemotherapy are the cornerstones of ovarian cancer therapy ... however, surgery in recurrent ovarian cancer has not been based on high-level evidence,” Dr. du Bois said. “So far there are only retrospective series suggesting that there might be a benefit or not.” The German AGO group and the Gynecologic Oncology Group (GOG) in the United States thus initiated clinical trials to evaluate its role in recurrent ovarian cancer, including the DESKTOP series, he explained, noting that the AGO score was developed through these trials as a way to identify good surgical candidates based on preoperative factors. It was confirmed in a prospective study that the score, which selects about 50% of all patients with platinum-sensitive recurrent ovarian cancer, could predict successful surgery, he added. In the current study, the data with respect to overall survival – the primary study endpoint – have not reached maturity, but at 2 years it was 83%. However, the findings of a meaningful benefit in progression-free survival and time to first subsequent treatment (advantages of 5.6 and 7.1 months, respectively) in secondary cytoreductive surgery patients is at least comparable with all phase III trials in second-line therapy for platinum-sensitive recurrent ovarian cancer so far, he said. “In fact, it’s the most positive trial ever reported in this population,” he added, noted that he was referring to therapy trials, not maintenance trials. Further, the fact that the surgery benefit was exclusive to patients with complete resection indicates the importance of selecting both the right center with capability of achieving complete resection in most patients, and the right patients, as identified by the AGO score. “Hopefully, further follow-up will show that this benefit translates into overall survival,” he concluded, noting that overall survival will be evaluated after extended follow-up when 244 overall survival events are observed. Dr. Du Bois reported serving as a consultant or adviser for AstraZeneca, Mundipharma, Pfizer, Pharmamar, and
Gynecologic Cancer
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Abstract
5501
Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (OC) has not been defined by level-1 evidence. Methods: Pts with OC and 1st relapse after 6+ mos platin-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were randomized to 2nd-line chemotherapy alone vs cytoreductive surgery followed by chemo. Chemo regimens were selected according to the institutional standard. We report here results of the predetermined interim analysis. Results: 407pts were randomized The TFIp exceeded 12 mos in 75% and 76% pts in both arms. 8.9% of 203 pts were operated despite of randomization to the no-surgery arm, whereas 6.9% of 204 pts in the surgery arm did not undergo operation. Complete resection was achieved in 67% of pts; 87% and 88% received a platinum-containing 2nd-line therapy. Median PFS was 14 mos without and 19.6 mos with surgery (HR: 0.66, 95%CI , p<0.001). Median time to start of first subsequent therapy (TFST) was 21 vs 13.9 mos in favor of the surgery arm (HR 0.61, 95%CI , p=p<0.001). PFS-2 between 1st and 2nd relapse equaled or even exceeded PFS-1 before 1strelapse in 26% after surgery and only 16% without-surgery. Analysis of the primary endpoint OS is kept blinded due to immaturity and will be evaluated after extended follow-up (the observed pooled unblinded 2-YSR was 83% instead of the initially in the protocol assumed 55-66%). 60d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparatomies were performed in 7 pts (3.5%) in the surgery arm.With the exception of myelosuppression which occurred more frequently in the no-surgery arm no further significant differences were observed with respect to grade 3+ acute adverse events. Conclusions: Surgery in pts with 1st relapse of OC after a TFIp of 6+ mos and selected by a positive AGO-Score resulted in a clinically meaningful increase of PFS and TFST with acceptable treatment burden. Until final OS data will definitively define the role of secondary cytoreductive surgery it should at least be considered as valuable option in pts with a positive AGO-Score. Clinical trial information: NCT

47. Take Home Points
Initial tumor burden and residual disease influence survival
Goal of surgery should be R0
Isolated, low-volume residual disease may be an appropriate alternative
Use ERAS® after surgery
Decreases complications
Improves patient satisfaction
May have cancer-related benefits
Routine removal of normal looking nodes at debulking surgery is unnecessary
Surgery for recurrent ovarian cancer improves progression-free survival

48. Thank You
Questions?