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

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

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

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

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

Initial Surgical Approaches

Primary Debulking Surgery Neoadjuvant Chemotherapy

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

There it is!!!

Now, remove it!!!

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

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.

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. 2015 Mar 10;33(8):937-43. 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. 2015 Mar 10;33(8):937-43.

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

This is complete resection (R0)

This is “optimal”

This is “optimal”

≠

Are all “optimal” patients the same?

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

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

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

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

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

Who has had a similar experience?

Don’t eat anything until you pass gas.

You will have IV fluids for the next few days.

We can give you narcotics for pain control.

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

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

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

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. 2016.Feb;140(2):313-22. 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. 2016.Feb;140(2):313-22.

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. 2016.Feb;140(2):323-32. 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. 2016.Feb;140(2):323-32.

Postoperative Fluid Therapy Postoperative IV fluids beyond 12-24 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. 2016.Feb;140(2):323-32.

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. 2016.Feb;140(2):323-32.

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. 2016.Feb;140(2):323-32.

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. 2016 Jul;40(7):1741-7. Elias KM. Anesthetic selection and disease-free survival following optimal primary cytoreductive surgery for stage III epithelial ovarian cancer. Ann Surg Oncol. 2015 Apr;22(4):1341-8. Gustafsson UO, Adherence to the ERAS protocol is Associated with 5-Year Survival After Colorectal Cancer Surgery: A Retrospective Cohort Study. World J Surg. 2016 Jul;40(7):1741-7. Elias KM. Anesthetic selection and disease-free survival following optimal primary cytoreductive surgery for stage III epithelial ovarian cancer. Ann Surg Oncol. 2015 Apr;22(4):1341-8.

Results From Recent Surgical Trials

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???

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). ]

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: NCT00712218.

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

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

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 2015. 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 Roche/Genentech.sworcester@frontlinemedcom.com Gynecologic Cancer    Comments (0) Recommended for You News & Commentary Four drugs better than three for myeloma induction VIDEO: Immune therapy effective, durable in treatment-naive melanoma brain metastases FDA approves nivolumab for metastatic CRC 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 2010-2014. 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 0.52-0.83, 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 0.48-0.77, 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: NCT01166737.

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

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