Bowel Obstruction in Advanced or Recurrent Ovarian Cancer

1. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer The 6th Chinese Conference on Oncology The 9th Cross-strait Academic Conference on Oncology Ming-Shyen Yen M.D. Chief, Division of Gynecology Department of Obstetrics and Gynecology Taipei Veterans General Hospital National Yang-Ming University May, 21, 2010

4. 台灣男女性十大癌症 (95年)

5. Age-standardized incidence of top 10 cancers for females over a 5-year period (2002-2006)

6. Age-standardized mortality rate for top 10 cancers for females over a 5-year period (2003-2007)

7. No. of new cases No. of deaths Breast 6895(49.99)* 1439(10.41)* Cervix (invasion) 1828(13.18)* 792(5.61)* Corpus 1159(8.45)* 135(1.00)* Ovary 1000(7.47)* 380(2.78)* Others 117(0.83)* 39(0.27)* Total 10999(79.92)* 2785(20.07)* Breast and Malignancies of Female Genital Tracts in Taiwan (2006) *age-adjusted incidence per 100,000 women

8. 台灣歷年卵巢癌症發生率(一)

9. (15.3﹪) (25.5﹪) (18.8﹪) (40.4﹪) TOTAL：5249 台灣歷年卵巢癌症發生率(二)

10. Ovarian Cancer • Patterns of Spread: • Direct extension to adjacent organs • By exfoliation and dissemination of clonogenic tumor cells throughout the peritoneal cavity • Via lymphatic system

11. General Treatment Strategy for Ovarian Cancer • Cytoreductive Surgery • Chemotherapy • Therapy for relapse : • Secondary debulking • 2nd-line chemotherapy • Intraperitoneal chemotherapy • IP P32 • Whole-abdominal radiation (WAR)

12. Patterns of Recurrence • Serologic relapse • Rising CA-125 only evidence of disease • Localized recurrence • Disseminated intraperitoneal disease • Extraperitoneal metastases • Recurrences can be symptomatic or asymptomatic

13. Treatment Considerationsin Recurrent Ovarian Cancer • Goals of therapy • Palliate symptoms • Prevent symptom development • Maintain quality of life • Increase progression-free survival • Prolong overall survival

14. Therapeutic Goals in Recurrent Ovarian Cancer • Manage symptomatic patients • Delay progression of disease • PFS • Increase survival • Maintain quality of life

15. Controversies in Recurrent Ovarian Cancer • Management of an asymptomatic rise in CA-125 in patients without evidence of disease on CT scan or on physical examination • Role of secondary cytoreduction • Optimal chemotherapy • Platinum-sensitive disease • Platinum-resistant disease • Use of in vitro sensitivity resistance assays • Determine length of treatment • Role of biologic/targeted therapy

16. Chemotherapy Principles in Recurrent Ovarian Cancer • Multiple agents have clinical activity • Activity superior in platinum-sensitive patients • Combinations are superior to single-agent platinum in platinum-sensitive patients • No established role for combinations in platinum-resistant disease • Management considerations • Length of treatment and “drug holidays” • Choice of combination in platinum-sensitive patients • Choice of drug in platinum-resistant patients

17. Surgical Management of Recurrent Ovarian Cancer • Secondary cytoreductive surgery • The standard management of patients with recurrence, particularly the role of surgery, remains poorly defined because of the absence of prospective randomized data. (wait GOG #213) • The longer the PFI, or the less residual disease after primary treatment, the better the patient’s performance status, the more likely that the patient will benefit from 2nd cytoreductive surgery. • Palliative surgery • The most common indication is malignant intestinal obstruction. • The management of malignant obstruction is challenging, not only because it usually occurs in the setting of recurrent, often drug-resistant, but also because there is a high morbidity and mortality associated with surgery. JCO, 25:2873-2883, 2007

18. Criteria for Consideration of Secondary Cytoreductive Surgery (SCRS) • Complete clinical response with a disease-free interval ≥6 months • Rising CA125 level and/or radiographic or physical findings suggestive of recurrence • Absence of unresectable extra-abdominal or hepatic metastases • Patient acceptance of post-SCRS adjuvant therapy • Absence of medical contraindications to SCRS • Performance status score ≤3 Eisenkop SM et al. Cancer 2000; 88: 144.

19. Secondary Cytoreductive Surgery Royal Hospital for Women, U.K. Survival Benefit - Risk Ratio Analysis Tay EH et al. Obstet Gynecol 2002; 99: 1008.

20. No residual Residual > 10mm Residual 1-10mm AGO DESKTOP- I OVAR Study: Surgery in Recurrent Ovarian Cancer (retrospective) Arbeitsciemeinschaft Gynakologische Onkologie Ovarian Cancer Study Group 2000-2003 N= 267 Median survival 45.2 vs. 19.7 mos Hazard Ratio (HR)= 3.71; 95% CI 2.27-6.05; P < 0.0001. Harter P, et al, Ann Surg Oncol. 2006

21. Role of Surgery in Ovarian Cancer • Category I Surgery: Initial surgical cytoreduction Interval surgical cytoreduction Cytoreduction after neoadjuvant chemotherapy • Category II Surgery: 2-look surgical reassessment Extent-of-disease surgical reassessment Secondary cytoreduction Palliative surgery

22. Surgery for palliation • Palliative surgery combined with local irradiation: • Cutaneous lesion: Supraclavicular or inguinal-node metastasis Abdominal wall metastasis • Resection of an involved organ: Liver, brain, lung to relieve pain or improve function • Surgery considered to relieve obstruction of the urinary tract or intestine The most common problem: “ Intestinal Obstruction ”

24. Malignant Bowel Obstruction (MBO) MBO is a complex problemoccurring particularly in cancer patients with advanced gynecological and gastrointestinal cancer 1. Epidemiology: Ovarian cancer – 5.5 to 42% Colorectal cancer – 4.4 to 24% Breast cancer, lung cancer, melanoma – 3 to 15% 2. Etiology: Benign – adhesions, radiation enteritis Malignant – single site, multiple sites, diffuse disease 3. Considerations: Single site vs Multiple sites Partial vs Complete Small intestine vs Large intestine

25. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer • Epidemiology: • Exact incidence: unknown • Retrospective studies: 20 – 50 % • Related to disease and result of prior therapy • Incidence from causes other than cancer: 5 – 24 %

26. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer • Etiology: • Progressive intra-abdominal tumor growth that leads to extrinsic occlusion of bowel lumen • Intraluminal occlusiondue to pelvic recurrences or mesenteric or omental masses • Intestinal motility problemswith functional obstruction due to the infiltration of the mesentery or bowel muscle and nerves (extensive intraperitoneal carcinomatosis) • Result of prior therapy : adhesionfrom prior previous surgery, IP C/T, or R/T

27. Partial or complete bowel obstruction ↑Bowel contractions to surmount the obstacle ↑Colicky pain Continuous pain Distension, Tumor mass, Hepatomegalia Reduction or stop of through-movements of intestinal contents Damage of intestinal epithelium Bowel inflammatory response with edema, hyperemia and production of PG,VIP,nociceptive mediators Nausea and/or vomiting Causes of Symptoms in MBO Bowel distension lumen contents Gut epithelial surface area Bowel secretions of H2O,Na,Cl

28. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer • Diagnosis: • History • Clinical symptoms • Physical findings • Supine and upright X-ray • Radiographic contrast of the small and/or large intestine • Abdominal CT scan • Ultrasound

30. Management of Patients with MBO • Influenced by : • Level of obstruction • Pattern of disease • Clinical stage of cancer related to prognosis • Prior anticancer treatments • Patient’s health • One of the most challengingclinical scenarios • Balancing the advantages and disadvantages of intervention with : • Their prognosis • Tumor biology • Quality of life

32. Management of Patients with MBO • Diagnosis and Initial Management • Problems with the Literature • When Not to operate: MBO form Generalized Carcinomatosis • Surgical Decision-Making in MBO : • Patient factors • Disease factors • Operative facotrs • Other treatment approaches • Stenting • Percutaneous decompression • Decision-Making in Palliative Care

33. Management of Patients with MBO Patient presenting with symptoms of bowel obstruction and a history of cancer Clinical assessment • Patient acutely ill: surgical emergency. Most patients with MBO ≠ surgical emergency • History of symptom Radiology assessment : CT +/- MRI • Diagnosis and cause of obstruction • Site: single vs multiple Large vs small bowel Partial (Most MBO) vs complete Patient factors Surgical decision making Technical factors Decision-making with patient and family

34. Patient factors Technical factors • Age : biologic / physiologic • Performance status • Stage of cancer: previous treatments, any anticancer treatment options • Malnutrition / cachexia • Concurrent illness • Ascites • Degree of invasiveness Interventional radiology Endoscopy Open laparotomy / laparoscopy • Anesthetic requirements • Risk of post-procedure complications Management of Patients with MBO

35. Management of Patietns with MBO • Surgical decision making : • Identify the symptom • Identify a surgical cause for the symptom: mechanical vs functional obstruction • Assess the realistic ability of an intervention to alleviate the symptom • Formulate recommendations: No obligation to recommend futile therapy • Decision-making with patient and family : • What do they understand about the disease? • What do they expect from the surgery? • Explain clearly the expected potential benefits of the intervention: Is this something that would be worth it to them given the risks? • Does this procedure fit with the goals of care?

36. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer • Conservative treatment: • Nasogastric tube drainage • Intravenous fluid hydration • Medical management: hyoscine butybromide, haloperidol, corticosteroids, somatostatin, morphine, parenteral nutrition for perioperative period • Percutaneous endoscopic gastrostomy (PEG) • Stents

37. Pharmacological treatment in inoperable MBO Drugs to control nausea and vomiting in MBO Antiemetics Antisecretory drugs Prokinetic drug Metoclopramide 60-240 mg/D SC in p’ts with partial occlusion and no colic Anticholingergic drug Hyoscine butylbromide 40-120 mg/D SC,IV or Hypscine hydrobromide 0/8-2.0 mg/D SC or Glycopyrrolate 0.1-0.2 mg t.i.d SC or IV Neuroleptic drug Haloperidol 5-15mg/D SC or Methotrimeprazine 6.25-50 mg/D SC or Prochlorperazine 25mg 8h PR or Chlopromazine 50-100 mg 8h PR or IM and/or Somatostatin analogue Octreotide 0.2-0.9 mg/day SC or Antihistamine drug Cyclizine 100-150 mg/D 8h PR or Dimenhydrinate 50-100 mg SC prn

38. Indications Problems Antiemetics Symptom control Metoclopramide Functional subobstruction Stop in definitive or complete obstruction Steroids Subobstructive states Symptom control Hyoscine Symptom control Octreotide Subobstructive states Symptom control Short-term NG Pts unresponsive to pharmacological treatment Temporary measure Uncomfortable for long-term use Pharmacological treatment in inoperable MBO Indications for the use of symptomatic drugs

39. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer (I) Conservative treatment • Percutaneous endoscopic gastrostomy (PEG) : • Symptomatic relief from a NG tube, not necessary for PEG • Only to patients with symptoms poorly controlled with medications and to those who are not imminently dying • Ascites as a relative contraindication, but no adverse events if ascites draine-out before placement of the PEG

40. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer (II) Conservative treatment • Stents : • Self-expanding metallic stent via fluoroscopy with or without endoscopy • Palliation for patients with single colonic obstruction in the left colon • Varying degrees of success for gastrodudenal, duodenal, and small bowel obstruction from malignant disease • No good published criteria to aid in the decision to stent on patients with MBO • The choice of treatment depending on patient factors, tumor factor, and a history of any surgery and/or treatment

41. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer (III) • Goal of treatment: • Palliative rather than curative measures • Improving the QoL with a limited life expectancy • Decision to attempt surgery: Extremely difficulty • Considered: • Successful palliation • Risk of repeat obstruction • QoL after the surgery • Ability for further chemotherapy • Rates of operative morbidity and mortality • Obstipation vs constipation ?

43. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer • Types of procedure: • Depending on intra-operative findings at surgery • Options included both intestinal bypass and resection • Poor characteristics of ideal surgical candidates: • Bulky carcinomatosis • Rapidly progressive disease • Multiple sites of obstruction • Poor performance status • Heavy treatment of multiple chemotherapy agents or radiation therapy • Massive ascites?

44. Management for intestinal obstruction

45. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer • Successful palliative surgery defined: • Survival > 60 days from surgery • Peri-operative mortality defined: • Death within 30 days • Operative morbidity: 7 - 64 % • Operative mortality: 4- 32 % • Median survival: 5 - 33 weeks • Heterogeneous • More dependent on response to chemotherapy than the surgery itself

46. Bowel Obstruction in Advanced or Recurrent Ovarian Cancer • A through discussion with the patient and her family • No prospective randomized trial in this setting • No strict, clear-cut guidelines for management • The most challenging decisions, and the decision to operate in gynecologiconcologist

47. Reoperative Surgery for MBOPreoperative Consideration ( I ) • Distorted Anatomy and Loss of Normal Tissue Planes • A thorough knowledge of normal anatomy • Depending on the prior surgery – distored fascial planes, thick adhesions, walled-off fluid collections, a Gordian knot-like configuration of small bowel, and ectopic positions of ureters • A thorough review of the prior operative reports • Knowledge of any prior postoperative complications • Potential Pitfalls and Complications • Timing of reoperative surgery • Enterotomies-- only one possible complication • Nutrition • Immuno-supplements -- enteral feeding, formulas rich in arginine, glutamine, and omega-3 fatty acids

48. Reoperative Surgery for MBO Preoperative Consideration ( II ) • Preoperative Adjuncts • A thorough knowledge of prior surgeries and postoperative courses • Tumor markers and additional preoperative imaging studies • Place bilateral ureteral stents routinely • Operative Technique • Positioning of the patient • Dilators or other long blunt instrument be placed transvaginally • Exposure in visualizing anatomy and proceeding safely through the exploration • Enter the peritoneal cavity in virgin territory

49. Reoperative Surgery for MBO Preoperative Consideration ( III ) • Literature review and retrospective studies: • Patients received benefits in both survival and QoL when operation is chosen and successful for MBO. • When pursuing surgical exploration, it is important to keep in mind all of the different options, including bowel resection with anastomoses, intestinal bypass, creation of stoma, lysis of adhesions, placement of gastrostomy or jejunostomy tubes, or any combination of these. • Unfortunately, there are times that carcinomatosisis so extensive that the only option is to open and close in order to avoid extensive iatrogenic injury. Multiple authors have tried to define parameters to help determine which patients will likely benefit from palliative surgical intervention.

50. 270 patients with epithelial ovarian cancer (1984 – 2005) 75 patients (28%) developed bowel obstruction University of Brescia, Venice, Italy