Ovarian cancer, okay, and ovarian cancer, 14,000 cases a year in the deaths per year in the U.S., and I think actually rising 200,000 worldwide. We are seeing an absolute avalanche of epithelial ovarian and other ovarian malignancies through the University of Rwanda Fellowship Program. Advanced disease, as everybody knows, traditionally treated with primary cytoreduction. Primary cytoreduction, you know, started in the 30s and was popularized by this landmark paper by Griffiths, and then, which was later repeated by Hoskins, you know, showing that survival was inversely proportional to the amount of residual cancer at the end of ovarian cancer surgery. But in the course of that, primary debulking surgery has its costs, as we know, and this is my colleague, Alex Melamed, in an article in JAMA Surgery, looked at primary debulking surgery in the gray versus interval cytoreductive surgery in the sort of tan or beige, whatever that is, and the probability of 90-day mortality based on age. And the mortality's, you know, somewhat low overall, but drastically starts increasing at age 60, and then drastically increases in about the mid-70s. And this curve continues to become steeper with increasing age, so that, you know, you can take out of this that probably operating on primary debulking on patients over age 80 may not be the best move. That, and a number of other reasons, as you know, the issue of the question of neoadjuvant chemo and interval cytoreduction was raised, so that chemo would be administered before surgery, shrink the tumor, increase the chance of complete successful cytoreduction, reduce the need for radical tumor surgery. There are now five randomized controlled trials comparing primary cytoreductive surgery to neoadjuvant. The first of them, though this formatting is weirder than I thought, the first of them was this neoadjuvant chemo versus primary surgery lead author, Vergoet, in the New England Journal in 2010. And they looked at 632 patients with stage 3c or 4 disease at primary debulking surgery versus women treated with neoadjuvant chemotherapy. And they found that the women, that the largest residual tumor, so there was one centimeter or less, in other words optimal cytoreduction, was in 40% of patients undergoing primary debulking surgery versus 80% of patients at interval debulking. Post-operative rates of adverse effects and mortality were higher after primary debulking than interval. The hazard ratio for death in the group assigned to neoadjuvant chemo followed by interval surgery as compared to the primary debulking group was 0.98. In other words, the survival was the same. Complete resection of all macroscopic disease, as you guys know, was the strongest predictor of overall survival, regardless of whether patients got primary or interval debulking surgery. And this is the famous graphs from the Vergoet article in the New England Journal. In the top panel, you see that overall primary debulking surgery in red versus neoadjuvant chemo in blue for these patients with very advanced stage 3c or 4 tumor, very bulky disease, survival was the same. And then in the bottom panel, we see that the primary debulking surgery, absolute top curve for patients who had optimal surgery, who had primary debulking, versus in blue, the patients with neoadjuvant chemo who had optimal surgery, that survival was the same. The curves separate a little bit, but they're statistically the same in the article. So now there was a meta-analysis of the largest four trials of neoadjuvant chemo versus primary debulking. And to do the short version, if we look at the overall effect, the balance, there's no statistical difference in survival between neoadjuvant chemotherapy in this left hand and primary debulking surgery. And the trend is definitely towards neoadjuvant chemotherapy in the clinical trials. And we see in multiple trials that the survival curves appear about the same. In the Cochran review, the overall survival was statistically the same. Progression-free survival was the same. And serious adverse effects, so that's very important, was 30% for primary debulking surgery and only 6% in the neoadjuvant chemo group. Rate of stoma creation was 20% in these high volume centers for primary debulking and 6% for neoadjuvant. And post-op death was quite significant, 3.6%. So over, you know, one in, what, 33 patients dying from their primary surgery. That means it'd be at least a woman a year, you know, in any of our programs. I had a patient recently, I was showing this to the team last winter, 58-year-old woman, G0, four-month history of increasing bloating and fatigue, unintentional weight loss, small caliber stools, history of breast cancer, also had substance use disorder. She looked wasted with a low body mass index, protuberant abdomen. She had inguinal adenopathy and a firm fixed pelvic mass and palpable rectal compression on digital rectal exam. And CT showed a big complex pelvic mass, large ascites, a right pleural effusion, liver with nodularity, consistent with cirrhosis, elevated CA125. And we got tapter ascites, just like Dr. Eugene's case. And we got adenocarcinoma, which was PAX8 and ER positive. And so here's the CT. And what I wanted to briefly show here was this sort of brain sign, right, that this is the loops of bowel should float up to the top of this liquid ascites because of the air enclosed in the bowel, but they're retracted. And so this is pretty much indicative of bulky mesenteric disease and unresectability when you see this on CT. Similarly, we just see huge ascites. We see a hiatal hernia with ascites in the hernia. And we see a bulky pelvic mass with compression of the rectum. And so, you know, what favors neoadjuvant chemotherapy for her? Well, not really her age, but major medical problems increase the risk, medical compromise due to her disease severity and likely unresectable disease. So what did we see in terms of, you know, what do we look for on that pre-surgical CT when we're deciding based on disease severity to do neoadjuvant versus primary debulking? So I think just to back up, we've got two major ways to select the neoadjuvant chemotherapy, right? One is the medically inoperable patient, the medically compromised patient, and one is a patient with an extent of disease that either indicates or strongly suggests that this won't be completely resectable at primary surgery. So speaking of that second group, we look for diffuse or deep infiltration of the small bowel mesentery, diffuse carcinomatosis, especially if it involves the stomach and large parts of the bowel, infiltration of the duodenum or parts of the pancreas, not just the pancreatic tail, involvement of the large vessels in the hepatoduodenal ligament, celiac trunk, or behind the porta hepatis, involvement of the liver parenchyma, especially deeply, lung metastases or lymph node metastases in the axilla or mediastinum. And then the other thing, Fogotti back in 2006 created a score based on laparoscopic or open assessment to determine resectability. And they looked at the following seven features, peritoneal carcinomatosis, diaphragmatic disease, mesenteric disease, omental disease, bowel infiltration, stomach infiltration, and liver mets. Each of those was given two points if it was positive or extensive and zero points if absent or limited. So they looked at 64 patients who had a diagnostic laparoscopy or a laparotomy and found that a score of eight or more. So if you had four of these things, positive or extensive, there was zero chance in their hands in this high volume center of getting an optimal surgery. MD Anderson did a prospective trial of that Fogotti score at diagnostic laparoscopy and XLAP by two surgeons. And if they disagreed, they got a third surgeon. So they looked at 226 patients undergoing a laparoscopic assessment of which 60% had basically a Fogotti score of less than eight and 36% had a score of over eight. Six patients were unscorable. There was 96% concordance between the Fogotti score at laparoscopy and the ability to do a total surgery. And the concordance by location between the laparoscopy and the ultimate surgery were as follows with bowel infiltration, 75%, mesenteric disease, 85%, liver surface involvement over 85%, omental disease and diaphragm disease, very high, stomach infiltration, very high, and carcinomatosis, very high. So patients at MD Anderson with a Fogotti score less than eight had an 85% chance of a complete surgery. So we would recommend then that you get, if you have a patient with apparent ovarian cancer, I apologize for going over time, everybody, that you do scanning if at all possible of chest, abdomen, and pelvis. Patients with stage one or two basically get surgery and chemo is indicated. Patients with apparent stage three or four get a laparoscopic assessment if possible, and then determine if the disease is resectable. If it is not, they get neoadjuvant disease. And then a repeat scan, ideally after three cycles, but we can discuss more. There is this question of, does the number of cycles before interval surgery matter? And lead author Marchetti, but this is again from Fogotti's group, did a retrospective study and found at their center with very skilled surgeons, there was no difference in outcome between patients having interval debulking surgery after three or four versus after more than four cycles of chemotherapy. So this may not be as important as we sometimes think, the timing of the interval debulking surgery. They also determined that patients ready for interval debulking surgery, they considered decreased tumor burden by CT and exam, resolution of ascites. They looked for a CA 125, less than 35, and for an acceptable surgical candidate. In other words, their nutrition status and their overall functional status, which would be based, particularly based on an ECOG score or frailty score. So, you know, additional considerations, patient's preference and frailty based on older age, limited physical activity, distress, like ongoing pain, more than four or five medicines, poor social support, functional dependency, you know, a patient who's in an institution, weight loss of greater than 10%, or certainly a patient with cognitive impairment. And Mayo Clinic created an algorithm, which is very reproducible in terms of evaluating the medical status of a patient prior to a cytoreductive surgery for ovarian cancer. They use this to determine whether to go to primary debulking or neoadjuvant, but I think it helps in terms of selection for interval debulking as well. So they avoided cytoreductive surgery if the albumin was less than 3.5, age over 80, or age of 75 with risk factors like ECOG score greater than one, stage four disease, or a high chance of complex surgery, for example, bulky rectal involvement. I'm just showing here that they had highly predictive algorithm for grade three post-op complications. They were able using that to decrease their complications, but in particular, to improve their, to decrease their 92-day mortality among patients who had these severe complications. So that went from 28% in the pre-intervention cohort to two and a half percent in the cohort after this algorithm. In other words, they weren't completely able to avoid complications, but they could avoid death from complications. And so timing of interval surgery, I look for normalization of CA125, resolution of ascites, response to solid tumors on CT, and improvement of their medical status, no unresectable disease on laparoscopy. And then if I don't have these things, I proceed to six cycles of chemo. After six, you have to decide if there's clear progression or persistence, you may move straight to second line therapy. But if it's a medically fit patient with a mixed response, like our patient Eugene describes, then I would consider a laparotomy to give that patient her best chance.

ovarian cancer

treatment options

primary debulking surgery

neoadjuvant chemotherapy

interval debulking surgery