OQ: Ovarian Cancer Upfront

Question 1

During an ovarian cancer staging for mucinous histology, is appendectomy necessary?

Answer 1

The upper and lower GI tract should be carefully evaluated to rule out an occult GI primary with ovarian metastases, and an. an appendectomy need only be performed in patients with a suspected or confirmed mucinous ovarian neoplasm if it appears to be abnormal. A normal appendix does not require surgical resection in this setting

Question 2

Describe the treatment arms, population subgroups, and median PFS for phase III RCTs testing PARP inhibitors for maintenance after first-line chemotherapy.

Answer 2

Question 3

How do you decide who to give neoadjuvant to. What patient factors, what disease factors

Answer 3

Assess 1) suitable surgical candidate (PS, nutrition/albumin, age, comorbidities, frailty); 2) appropriate candidate for NACT (extent of disease, surgical debulkability)

Fagotti score- 7 parameters: omental caking, peritoneal carcinomatosis, diaphragmatic carcinomatosis, mesenteric retraction, bowel and/or stomach infiltration, and liver capsule metastasis. Each parameter is scored with a value of two points. In the updated model, a score of ≥10 identified patients had a 100% sensitivity for patients who could not possibly obtain R0, with an only 42% rate of optimal debulking, less than this was 83% and contained all the R0 cases.

Frailty index- Mayo. The FI includes 30 items scored at 0, 0.5, or 1 and is calculated by summing across all the item scores and dividing by the total. Frailty was defined as a FI ≥0.15. 25% considered to be frail. Frailty associated with worse OS ((median 26.5 vs 44.9 m, p b 0.001). and worse surgical outcomes. Some items include: need help with self care (toileting, brushing teeth, walking, feeding, dressing etc), assistive devices, 2 flights of stairs, medical comorbidities..

Question 4

How do you decide open laparotomy vs minimally invasive technique?

Answer 4

Surgical guidelines emphasize that open laparotomy should be used.

MIS can be used for early stage disease- no diff in surgical outcomes, recurrence rates, survival

IDS- studies show that its safe, technically feasible and can achieve optimal cytoreduction

Need to convert to xlap if optimal debulking cannot be achieved using MIS techniques

Question 5

Do you use laparoscopic evaluation prior to resection?

Answer 5

Yes: to evaluate extent of disease and feasibility of resection

Fagotti- RCT- if lapsy would be useful to predict optimal debulking- R1 achieved in 90% with lapsy vs 61% without assessment

Assessment laparoscopy required for SCORPION trial (Fagotti)

No- use imaging to guide my decision

I think safe answer here is I use both imaging and laparoscopic evaluation to inform what is, in the end, a clinical decision.

“Modified Fagotti: This was a study of 234 patients who underwent laparotomy with the intent of cytoreductivesurgery after having undergone a laparoscopic evaluation to assess extent of disease or tumor burden. The authors noted that optimal cytoreduction (R0) was achieved in 57.5% of patients. At a PI > 10, the chance of achieving complete cytoreduction was 0 and the risk of unnecessary laparotomy was 33.2%. The authors concluded that the updated PI led to a lower rate
of inappropriate laparotomic explorations at the established cut-off value of 10.” Ramirez

Question 6

When do you consider fertility sparing options? What is the fertility sparing option?

Answer 6

• Stage 1 epithelial ovarian cancer (except for clear cell- controversial)- large retrospective/meta-analysis- didn’t compromise dfs or OS compared to radical surgery
• All stage borderline tumors
• All stage germ cell
• Stage I sex cord stromal tumors
• USO (BSO if stage IB), comprehensive surgical staging => will upstage 30% with early stage disease.
• Pediatric/adolescent patients- can omit surgical staging in early stage germ cell tumor - similar outcomes

Question 7

What entails a comprehensive staging procedure?

Answer 7

1. Tah, bso, pelvic washing, omentectomy
2. Systemic lymphadenectomy for IIIB or less- RCT- improves detection of metastatic nodes compared to sampling (22 vs 9%) but doesn’t improve PFS/OS.
   a. Meta-analyses- LND in early-stage improves OS, not PFS
   b. Advanced stage IIB-IV- LION RCT, pts who had R0, normal nodes both before and during surgery, LND didn’t improve PFS/OS and associated with postop complications and mortality. Found microscopic LN mets in 56%
   c. Can guide adjuvant therapy - ACTION trial found if comprehensive staging of St1-2 pts, chemo did not improve survival, but it did if the pts were not fully staged.

“the long-term analysis of the ACTION trial data 1) substantiated the original findings of the ACTION trial that the completeness of surgical staging in early ovarian cancer is an independent prognostic factor for recurrence-free and overall survival, even when adjuvant chemotherapy is given after surgery and 2) substantiated the original conclusion of the ACTION trial that “ … the benefit of adjuvant chemotherapy appears to be limited to patients with non-optimal staging, i.e., patients with more risk of unappreciated residual disease”

Question 8

What chemotherapy do you give for adjuvant chemotherapy or nact?

Answer 8

1. Carbo/taxol
   a. Several randomized trials compared carboplatin vs cisplatin- similar efficacy but better QOL for carboplatin
   b. Carbo- more thrombocytopenia/neutropenia
   c. Cisplatin- neurotoxicity, nausea/emesis, renal toxicity, metabolic toxicities, anemia, alopecia
2. carbo/docetaxel- SCOTROC- similar PFS/OS, QOL- lower neurotoxiity, alopecia, myalgia, but higher peripheral edema, allergic reactions
3. carbo/doxil (auc 5, doxil 30mg/m2 q 21 days) - MITO2- similar PFS/OS but worse qol- higher hematologic toxicities, skin and stomatitis, lower neurotoxicity and alopecia
   a. For select pts who want to avoid alopecia or high risk for neurotoxicity

Question 9

EORTC neoadjuvant trial, what are criticisms of that trial

Answer 9

1. Vergote- Stage 3/4, NACT vs pds. No diff in pFS/OS. Shorter operative time 165min. More R0 and optimal cytoreduction, less postop deaths. Less morbid
2. Criticisms- not all gyn onc surgeons, short OR times, low R0 rates esp in PDS group (R1 pds 47% vs nact 81%) , shorter survival than U.S. (PFS 12, OS 30 mos vs 50 mos in US- if do cross trial comparison in US, like GOG 218)

Question 10

How many cycles/what type of neoadjuvant do you give. You do optimal interval debulking, what adjuvant chemo do you give?

Answer 10

1. IV taxol/carbo x3-4 cycles. Can give up to 6 if responding to it
2. IV- EORTC 55971 (non inferior), CHORUS (non inferior), SCORPION (superiority), JCOG0602
   a. R0 PDS better than R0 NACT. retrospective trials
   b. NACT better for Stage IV
   c. 25% of PDS arm didn’t get good upfront debulking=
3. IP- GCIG OV21/PETROC. (where is the trial done? Canada) Terminated after the phase II because of poor accrual- The 9-month progressive disease rate significantly better in the IP carboplatin arm vs IV arm (25 vs 39%). No IP cis in final analysis bc did not meet pre-specified superiority cut off. Underpowered for PFS/OS.
4. If give Bev for NACT- stop for 6 weeks per NCCN; Bev given in neoadjuvant setting in multiple RCT’s (gog 262- dose dense with/without Bev, nact allowed,stage 2)
5. Minimum 6 cycles, At least 3 cycles for adjuvant per NCCN

Question 11

Do you follow CA-125 for surveillance, why/why not?

Answer 11

1. RUSTIN, MRC OV05/EORTC 55955 - treating recurrences early based on ca125 in asymptomatic patients was not associated with increase in survival and associated with decrease in QOL.
2. What is the criticism of that trial- Morris Lancet 2010- Different definitions of PFI- 20% had platinum resistant and 34% had platinum sensitive; contemporary therapies not available to most pts, like Bev and doxil (trial started in 1996); 45% had PFS greater than 12 months but only 7% had surgical intervention. *** trial carried in an era where they did not consider secondary debulking or targeted therapies/parp as a maintenance strategy to lengthen disease control/survival
3. Yes - b/c its an easy marker to detect recurrence without frequent imaging and symptoms can still be vague to detect recurrence. Don’t necessarily treat at first increase - can wait til symptoms or if large disease on CT. Also early detection may make patient a surgical candidate if isolated lesion.
4. No- treat based on symptoms not CA125 b/c can be elevated and no visible disease and survival same, QOL better if you wait
5. Can treat asymptomatic pts with elevated ca125 with tamoxifen

Question 12

What’s the data for IV/IP chemo for stage II.

Answer 12

1. NCCN rec is for stage II-III
2. GOG 252- stage II-IV, sub and optimal- 10% of study was stage II
   a. IP cis 75 less effective than 100
   b. IP carbo equivalent, IV dose dense equivalent
   c. All had Bev 15 mg/kg from cycle 2-22
   i. Arm 1: Day 1, 8, 15 IV taxol 80mg/m2, D1 iv carbo auc 6
   ii. Arm 2: D1, 8, 15 iv taxol 80mg/m2, d1 IP carbo auc 6
   iii. Arm 3: D1 iv taxol 135mg/m2, D2 ip cis 75mg/m2, D8 ip taxol 60mg/m2
   d. PFS 28 mos all arms, 32-33 mos if R0

Question 13

Dose dense taxol, when do you give it?

Answer 13

JGOG 3016- OS 100 vs 62 mos; suboptimal appeared to benefit the most - improved PFS and OS; no benefit for R0-1

GOG 262- C/T q3 wks vs dose dense. Bev given to 84% pts. Dose dense only benefited pts with no Bev (14 vs 10 mos)

ICON8 (Europe)- q3 wks vs weekly carbo/taxol (80mg) vs dose dense- no diff in PFS in all arms. Dose dense had higher toxicity and decreased QOL.

SAE-higher anemia and neuropathy, lower neutropenia- compared to q21day cycle

Question 14

How do you give IV/IP, what’s the data for dose-modification? What anti-emetics do you use?

Answer 14

1. NCCN- D1 IV pac 135 over 24hrs, D2 cis 75-100 IP, D8 pac 60 IP
2. IV hydration before and after and 5-7d as outpatient
3. Zofran 30 min IV pre chemo and PRN post op, Emend- 1 day before and 2 after, dexa prechemo PO/IV

Question 15

What do you do for someone getting grade 2 neuropathy with IV/IP on cycle 3, it’s worse after cycle 4, what do you do. Is it the cisplatin or paclitaxel causing it? What’s the data for switching to docetaxel.

Answer 15

1. Combo, cis/taxol has about 12% G3/4 neuro rate
2. SCOTROC1- taxol 30%, docetaxel 11% neuropathy
   
   1. Stage I-IV EOC, survival and ORR equivalent
   2. Docetaxel has more neutropenia, peripheral edema, gi toxicities
3. GOG 172- Grade 2 Neuropathy- decrease IP cisplatin dose to 75mg?; if Grade 3, postpone treatment

Question 16

Suboptimally debulked mucinous ovarian cancer, what chemo do you give. What else besides taxol/carbo can you give up front?

Answer 16

1. Would try FOLFOX +/- Bev
2. Oxaliplatin + capecitabine
   
   1. Oxaliplatin (alkylating agent, binds to dna forming cross links- inhibits dna Replication and transcription) 130 mg/m2 IV d1 (2 hr infusion, 6 hr for acute toxicities)
   2. Capecitabine (undergoes hydrolysis in the liver to form fluorouracil, inhibits thymidylate synthetase, interferes with DNA) oral 850mg/m2 BID, Day 1-14 of a 21 day cycle. Contraindicated if CrCl <30 ml/min
   3. SAE: emetogenic, neutropenia, hyperbilirubinemia (capecitabine), diarrhea, hand foot syndrome (capecitabine)
   4. Caution: capecitabine: pts with DPH (dihydropyrimidine dehydrogenase) enzyme mutations are increased risk of early, severe, fatal toxicities. Age related deficiency. Start at lower dose in elderly. Caution with warfarin use as well.
3. Gem+ oxaliplatin
4. BRAFi
5. Kurnit 2019 (MDA)- 52 pts retrospective; gi chemo more likely to receive bev 50%; gi chemo had improved PFS and OS
6. Dose dense- no data for mucinous specifically, increase toxicity, prob not worth the benefit

Question 17

Low grade serous carcinoma case list pt, I gave IV/IP to her. Asked what’s the data. Are low grade serous carcinomas different from high grade.

Answer 17

No IP RCT included low-grade serous carcinoma

Question 18

41 yo debulked for clear cell carcinoma, asked about DVT prophylaxis, specifically if anything is different for clear cell carcinoma

Answer 18

Higher risk (42%), but no data to do anything different, no NCCN guideline

Question 19

Early ovarian cancer treatments by stage/grade?

Answer 19

1. HGSOC- 6 cycles for all (GOG 157 and NCCN)
2. LGSOC- obs for 1a/1b, 1c- 3-6 cycles (Gershenson- f/b hormonal tx)
3. G2/3 Endometrioid, CCC- 3-6 cycles for all stages
4. G1 endometrioid - obs for 1a/1b
5. Mucinous - 1a/1b obs, 1c- 3-6 cycles
6. GOG 157- no benefit for 6 vs 3, Chan update shows PFS benefit for 6 cycles for HGSOC only
   
   1. GOG 157- superiority trial, eligible- Stage IA/B, grade 3, all clear cell, all Stage IC/II. 6 cycles not better than 3. They already have great outcomes, so 6 cycles did not show better results, more toxicity, more inconvenient for patients. GOG 175- taxol maintenance x 6 cycles, did not show better outcomes in early stage ovarian cancer. Criticisms: powered to reduction by 50% of addition of 3 more cycles. Overestimated benefit of 3 additional cycles. Not enough patients. Reported too early. 30% were unstaged- studies show that completely staged pts may not need adjuvant chemo so 3 vs 6 cycles will not show difference , conclusions not powered for subgroup analysis (staged vs unstaged) Argument for 6 cyles- Additional toxicities of 6 cycles are not much worse than 3- already have alopecia, transient SAE. Cure for ovarian cancer is in upfront setting.
   2. Chan- retrospective subgroup analysis of GOG 157- 6 cycles better for serous. Criticism: not powered, Not RCT, biased, unbalanced groups, no analysis on BRCA status.

Question 20

Pap serous ov ca – genetic counseling topics, risks, tests done

Answer 20

1. BRCA1/2, HRD
2. 20, 40% risk of ov ca
3. BRCA1 - risk of USC ~2%

Question 21

IP dosing and indications

Answer 21

1. Stage II-IV, optimal debulking

Question 22

Molecular differences between low and high grade ov ca

Answer 22

Low - KRAS, BRAF, MEK

HGSOC- p53, p16, high Ki67

Question 23

Management of early ovarian cancer – who gets full staging? Why? What trials point to this?

Answer 23

1. Multiple studies show that 30% of presumed early-stage disease are upstaged after undoing complete staging and up to 35% required adjuvant treatment (Richard Young NEJM- retrospective, what studies)
2. Can omit chemo if no metastasis
3. Mucinous infiltrative- 30% of LND mets

Question 24

Describe your process of lymphadenectomy. What artery are you going to take down if you do a debulking LAD? What are the complications of ligating the IMA? In what patients would you worry about complications from this? What is the complication rate for full lymphadenectomy and what are the complications? Do you do full LAD for every ovarian cancer case? Or does it depend on grade, histology, etc? What studies tell you why or why not to do this?

Answer 24

(IMA)

(bowel ischemia)

(10-20% lymphedema, 22% postop ileus, vascular injury

1. Early stage- RCT showed that it upstaged but didn’t improve PFS/OS (Maggioni, 2006- 268 eligible patients , 22% had positive nodes. Other meta-analysis showed that LND improves OS, although not PFS, found 3-14% had positive lN
2. Advanced stage- LION- RCT- LND didn’t improve PFS/OS, increased postop complications and mortality within 60 days. Other meta-analysis show that LND improves OS but not PFS
3. NCCN- recommends LND up to stage IIIB; PALND at least to IMA, preferably to renals

Question 25

How do you manage BRCA 1 and BRCA2 patients? When do you offer them oophorectomy? In what circumstance would you offer a BRCA2 patient to have the BSO later than 35-40? Describe the operation in detail. Do you follow BRCA 1 any differently from BRCA 2? How do BRCA carriers respond differently to platinum? Why (synthetic lethality)? What other drugs are available to them (parp i)? Why do these work well in BRCA carriers? Know the whole mechanism in detail. Recite it over and over again to yourself. They will make you do it. How will you manage hot flashes for these young patients after BSO.

Answer 25

For women with a BRCA1/2 pathogenic variant who do not opt for bilateral mastectomy, we suggest surveillance with annual mammography and magnetic resonance imaging (MRI). We initiate MRI at age 25 and mammography at age 30. For female BRCA2 carriers who do not opt for risk-reducing mastectomy, we suggest endocrine therapy for chemoprevention with AI or SERMs.

For women with a BRCA1/2 pathogenic variant, we recommend rrBSO between age 35 and 40 for BRCA1 carriers and between 40 and 45 for BRCA2 carriers, when childbearing is complete. For screening prior to rrBSO, we offer concurrent transvaginal ultrasound and cancer antigen (CA) 125 q 6 months starting age 30.

BRCA genes- required for homologous recombination, which repairs DNA double-strand breaks. BRCA1/2 patients respond better to platinum because the impaired ability of BRCA-deficient tumor cells to repair platinum-induced double strand breaks, which confers increased sensitivity to chemotherapy

Parp (Poly ADP-ribose polymerase)- repairs single-stranded dna breaks mainly through the base-excision repair pathway. PARP inhibitors result in double stranded breaks that cannot be repaired by BRCA-deficient tumor cells, leads to synthetic lethality through accumulation of DNA damage that results in cell death.

Hot flashes with surgical menopause- Gyn onc review- can prescribe HRT - observational studies demonstrate no increased risk in women prior to mastectomy but small and few, still a theoretical risk. Consider nonhormonal options, limiting duration, concomitant hysterectomy to avoid progestins.

Occult malignancy during RRSO 5%

Question 26

What type of breast cancer is typically associated with BRCA mutation? Is there a difference in ER/PR/HER2-neu expression in breast cancers associated with BRCA1 vs BRCA2? What breast screening do you offer for BRCA carriers?

Answer 26

brca1/2 associated with triple negative breast cancers- higher in BRCA1 pts

Screening- RRBSO, poss hyst for brca1. Brca1 age 35-40; brca2 age 40-45; pelvic u/s with ca125 q 6 months if no surgery

mammo/MRI q 6 months- 25 y/o

Self breast exam- no data to recommend but little harm

Question 27

How do you treat a patient with a STIC lesion? What is the risk of actually finding cancer in these patients on follow up RRSO surgery?

Answer 27

1. NCCN- obs alone with or without ca125 testing vs surgical staging with obs (no LND) or chemo if invasive cancer is noted.
2. Occult cancer in 5% undergoing RRSO.
3. Primary peritoneal cancer 1-2%
4. Decreases breast cancer by 50%

Question 28

What are your options for adjuvant treatment (i.e., IV/IP, dose-dense, standard)? What IV/IP regimen do you use (they asked me to state the exact doses and schedule) and what trial supports using IV/IP? What were the outcomes of that trial (GOG-172)? How do you interpret the results of GOG-252? What data supports the use of dose-dense paclitaxel and carboplatin? Which patients did not benefit from dose-dense chemo?

Answer 28

1. IV/IP
   
   1. If yes: Still do IP in patients in microscopic disease because there are 3 positive RCT GOG 104, 114, 172- showed survival benefit compared to IV therapy. I know that there are concerns with IP with GOG 252. No good control arms.
   2. If No: GOG 252 was a definitive trial. All other trials didn’t look at BRCA status. GOG 172 showed that 50% of people didn’t get through 6 cycles because was too toxic. With new novel therapies with parp and maintenance, especially in BRCA patients, and with the latest IP study showing no benefit, I think IP therapy will be challenging due to toxicities and that’s how i dictate my practice.
   3. GOG 114- used carbo AUC 9; improved PFS (28 vs 22 mos); and OS (63 vs 52 mos); first trial to add taxol
   4. GOG 172- improved PFS (24 VS 18 mos) and OS (66 vs 50 mos); criticism- higher dose of cisplatin in IP arm, dose dense schedule of taxol; carboplatin not used in IV arm
   5. Combined 114 and 172- improved antiemetics delivered 85% of planned iv/ip. If R0 at completion of initial therapy, median OS 110 mos
   6. GOG 252- included stage 2- Bev in all arms- no diff between PFS and OS across arms. Concl- IV carbo/taxol/bev was supported. Criticism- lower cisplatin dose, 3 hr taxol, bev used. Final analysis- trend towards IP cis arm but not significant
      
      1. Criticism: no good control arm- they got BEV in all arms, not standard of care. IP arm got cisplatin 75mg which is lower than other IP trials- underdosed. Included suboptimal group, which was not allowed in other IP trials. Bev washed out effect of IP.
   7. BRCA mutations have improved outcome with iv/ip compared with iv therapy- no prospective trials, retrospective data only but did not get treated with PARPs, maybe benefit of IP therapy will be washed away with PARP
2. Dose dense
   
   1. JGOG 3016- OS 100 vs 62 mos; suboptimal appeared to benefit the most - improved PFS and OS; no benefit for R0-1, no benefit for mucinous/clear cell?
   2. GOG 262- C/T q3 wks vs dose dense. Bev given to 84% pts. Dose dense only benefited pts with no Bev (14 vs 10 mos)
   3. ICON8- q3 wks vs weekly carbo/taxol vs dose dense- no bev, no diff in PFS in all arms. Dose dense had higher toxicity and decreased QOL.

Question 29

When do you use Bev? What is the data to support Bev as part of adjuvant therapy? Go through the trials and analyses.

Answer 29

1. GOG 218- 4 month improved PFS- greatest diff around 15 months, exploratory analysis- Bev had long PFS (15.4 VS 10.6 mos) in patients with WT BRCA/HRP
2. ICON7- no diff in PFS/OS, diff peaks around 12-18 mos then converges
3. Poor prognosis benefits best; gog 218- stage IV and ascites, suboptimal- improved OS; ICON7- high risk includes stage IV, inoperable stage III, suboptimal- improved PFS/OS

Exclusion criteria for bev- serious non-healing wound, ulcer, or bone fracture; history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days; active bleeding or known bleeding disorder, coagulopathy, or tumor involving major vessels, Uncontrolled hypertension, 150/90, History of CVA, clinically significant proteinuria; UPCR > 1.0 (equivalent to 1g protein in 24hr urine collection), gastrointestinal obstruction

Question 30

How long would you continue Avastin maintenance?

Answer 30

Gog 218- up to cycle 22; ICON up to cycle 18

Question 31

What if 6 months after Avastin, patient develops headache and elevated BP. What would you do?

Answer 31

1. Stop Bev or start BP med
2. Ace inhibitors dilate efferent arteriole → protect from proteinuria
3. Ask for other symptoms - r/o PRES- hypertensive emergency, visual changes, n/v, => MRI

Question 32

Bevacizumab: side effects.

Answer 32

1. HTN 1/3rd (24-42%), proteinuria 5-20%, vte, wound healing, bleeding
2. What is the risk of GI perforation. 2%- seen with IBD and bowel resection at primary surgery (GOG 218)
3. PRES <1%- seen in GOG 218

Question 33

SOLO1: what is PFS and OS. How long would you keep on PARP inhibitor? Most concerning toxicity?

Answer 33

1. HR 0.33, PFS 56 months vs 13.8 mos (placebo), OS not ready
2. 5 yr progression free- 48% vs 20.5%
3. Continue until progression or toxicity or 24 months
4. MDS/AML 1-2%

Question 34

Who do you test for Germline mutation? When? Somatic? Why?

Answer 34

1. All epithelial ovarian cancers at diagnosis
2. 5% of germline is missed with somatic testing- myriad picked up 5% more than foundation 1

Question 35

Will you put an IP port in on a bowel resection?

Answer 35

UTD: “We place an IP port at the time of debulking surgery that includes bowel resection. In this scenario, we prefer to give the first cycle of chemotherapy intravenously (IV) and start the IV/IP regimen with the second cycle. Giving IV chemotherapy initially allows for complete healing of the bowel anastomoses before initiating IP chemotherapy. If the patient tolerates treatment well, she will receive six cycles of IV/IP chemotherapy (making a total of seven cycles of adjuvant chemotherapy).”

Question 36

Drawing of patient with IP chemo. How is it given? How do you counsel patients. On cycle 4, patient has erythema around port after Day 8 taxol (shows picture of port with sutures - this really threw me since it was cycle 4, but they wanted you to see the “redness”). What imaging do you do? What treatment do you give? Do you continue IP? When to remove?

Answer 36

1. IP chemo- supine, reposition q 15 min during treatment
2. Side effects- cytopenia, n/v, port complications, abdominal pain, renal toxicity- cisplatin induced- hydration before and after
3. Infection- antibiotics, continue IP, remove if not improving, r/o peritonitis

Real diagnosis they are talking about is extravasation.

UTD: “Replacement of a malfunctioning port will allow approximately 50 percent of patients to complete their planned IP therapy. Among the indications for removal of the port and catheter are intraabdominal infection, bowel injury, and non-remediable catheter blockage (such as retrograde flow of dye into the port pocket or at the point where the catheter perforates the peritoneum)”

Question 37

Risk-reducing hysterectomy in BRCA + patients. Would you do it and when/why?

Answer 37

UTD: “The only proven risk-reducing procedure for ovarian cancer in BRCA1/2 mutation carriers is rrBSO. We do not routinely recommend hysterectomy at the time of rrBSO unless other indications for this procedure exist. Moreover, there are no national guidelines that recommend routine hysterectomy in BRCA1/2 mutation carriers. While studies have reported a possible small, excess risk of uterine cancers in mutation carriers, the absolute risk is low, and it is not clear that the benefits associated with hysterectomy are sufficiently large enough to warrant the risks associated with surgery. While hysterectomy is not indicated to reduce cancer risk, some carriers may, however, choose to undergo this surgery at the time of rrBSO in order to enable them to take unopposed estrogen HRT without increasing their risk of endometrial cancer. It is therefore critical to have at least an initial discussion about these options preoperatively.”

Question 38

Hypersensitivity for platinum and taxol - memorize treatment for reaction and how to do desensitization

Answer 38

1. Mild or moderate (g1-2)
   * ​stop infusion, check ABCs and mentation, IV 50 mg of diphenhydramine for symptoms. Once symptoms have resolved, resumption of the drug infusion at a slowed rate may permit treatment continuation with close monitoring.
2. Severe or anaphylaxis:

●Immediately discontinue drug infusion

●Place the patient in the supine position with legs elevated (if tolerated)

●Assess airway, breathing, circulation, and adequacy of mentation

●Call for help (summon a resuscitation team in the hospital setting, call 911 or an equivalent service in the community setting)

●Administer intramuscular epinephrine into the anterolateral thigh (0.3 to 0.5 mg aqueous epinephrine, 1:1000 dilution)

●Establish IV access with two 14 to 16 gauge catheters

●Administer both an H1 (eg, 50 mg of diphenhydramine) and an H2 (eg, 20 mg of famotidine) antihistamine IV

●Systemic administration of a glucocorticoid (eg, 40 to 80 mg methylprednisolone IV) may not help acutely, although it may prevent a prolonged or recurrent reaction.

Question 39

PRES for bev, mgmt.

Answer 39

1. G4 toxicity → permanently discontinue and supportive care (BP control)
2. headache, confusion, visual symptoms, and seizures.
3. Typical MRI findings are consistent with vasogenic edema in the subcortical white matter and are predominantly localized to the posterior cerebral hemispheres
4. Stopping the offending agent and treatment of hypertension is the mainstay of treatment in patients with RPLS

Question 40

how you decide on chemo for first line, maintenance - more your general approach and options…

Answer 40

1. FIRST LINE FOR ADVANCED OVARIAN
2. Carbo/taxane backbone
3. Consider IP if optimally debulked stage 3
4. Consider dose dense if suboptimal after surgery (unless adding bev)
5. Bevacizumab for stage IV or poor prognosis stage III (ICON 7 –stage IV, suboptimal stage III, inoperable stage III) ,
6. GI based regimen for mucinous
7. weekly carbo auc2/taxol 60mg/m2 for frail ppl (MITO7)
8. carbo/doxil (MITO 2)
9. Carbo alone has worse prognosis compared to combination
10. MAINTENANCE
11. continue bevacizumab for anyone (22 cycles GOG 218, 18 cycles ICON 7)
12. olaparib for BRCA+ or somatic BRCA mutation
13. nirparib for anyone
14. olaparib + bevacizumab for HRD or BRCA+ (PAOLA)

Question 41

Know the HRD mutations and testing:

Answer 41

1. My Choice- bRCA1/2; GIS score (Loss of heterozygosity LOH, telomeric allelic imbalance TAI, large scale state transitions, LST) >42 (PRIMA, PAOLA)
2. Foundation One- BRCA ½; ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L alterations

Question 42

GOG 218- outcomes, #’s- final analysis OS , median f/u 102 mos

Answer 42

1. Stage 3/4, incompletely resected, R0 5%
2. 1)carbo/pac/placebo=>placebo vs 2) carbo/pac/bev => bev vs 3)carbo/pac/bev => placebo
3. PFS 10.3 vs 14.1 mos (sig)
4. OS 39.3 vs 39.7 mos (NS)
5. Stage 4; OS 42.8 v 32.6 mos- sig
6. BRCA 1/2 not predictive of bev activity

Question 43

Metastatic colon to ovary IHC markers?

Answer 43

CK 7 neg & CK 20 pos

Question 44

Kras mutation in which ovarian histology, BRAF mutation in which ovarian tumor?

Answer 44

Mucinous. LGSOV.

Question 45

Location of fallopian tube cancer in BRCA pts?

Answer 45

Fimbria.

Question 46

Most common mutation in fallopian intraepilelial lesions?

Answer 46

p53

Question 47

Breast Screening for BRCA pt?

Answer 47

Annual MRI & mammogram q 6 mos alternating from age 25

Question 48

Patient progresses on PARP-i, should parpi therapy for EOC be repeated over the course of treatment?

Answer 48

Repeating PARPi therapy is not recommended at this time because it is not supported by data. The lack of OS benefit from any of the treatment/maintenance studies to date should be balanced against factors such as AML and development of resistance to other agents

Question 49

When should you switch PARP therapies?

Answer 49

1. Switching parp to address tolerance is acceptable
2. Not acceptable to switch to a different PARPi at the time of disease progression

Question 50

Is Parp monotherapy recommended for recurrent EOC? In which settings? At what dose and duration?

Answer 50

1. PARPi monotherapy maintenance (second-line or more) with platinum-sensitive EOC following PR/CR to platinum based chemotherapy regardless of BRCA mutation status; treatment is continued until progression of disease or toxicity despite dose reductions and best supportive care.
   
   1. ​Olaparib (SOLO-3), 300 mg PO BID, continue treatment until disease progression or unacceptable toxicity.
   2. Rucaparib (ARIEL-3), 600 mg PO BID, continue treatment until disease progression or unacceptable toxicity.
   3. Niraparib (NOVA), 300 mg PO qday unless weighing <77 kg (<170 lbs) OR with a platelet count <150,000/mcL, then 200 mg PO qday, continue treatment until disease progression or unacceptable toxicity.
2. For the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)
   
   1. Niraparib (QUADRA), until disease progression or unacceptable toxicity
3. For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
   
   1. Olaparib (STUDY 42), until disease progression or unacceptable toxicity
4. For the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies.
   
   1. Rucaparib (ARIEL-2), until disease progression or unacceptable toxicity

Question 51

How do you manage PARP toxicities? Anemia, Neutropenia, thrombocytopenia, cytopenia, nausea?

Answer 51

1. Anemia- blood transfusion for Hb <8
2. Neutropenia- hold dose if grade 4 lasting >5-7 days or grade 3 associated with fever. Then reduce dose. Growth factor support may be used. Restart parp after fever resolves, anc >1,000, 48-72 Hrs after last dose of growth factor
3. Thrombocytopenia- most common with niraparib. Hold dose if grade 3/4 . Discontinue if persistent despite dose reduction. Start with Niraparib 200mg for Plt <150,000 and wt <77kg.
4. Cytopenia- evaluate for MDS/AML
5. Nausea- especially first cycle- recommend light meal or snack before taking parp. reduce if need daily antiemetics, PS reduction, >5% weight loss
6. Any grade 2 - hold dose, then reduce dose. Don’t re-escalate or resume initial dose

Question 52

Do you recommend HIPEC to your patients? If yes, for what indication?

Answer 52

1. Cisplatin 100mg/m2 for 90 min
2. Upfront debulking- no completed prospective trial
   
   1. Unpublished korean phase 3 (Lim et al, ASCO)- upfront and interval settings- 56 patients, no diff in PFS/OS between HIPEC vs control. Criticism: small number, heterogenous pt cohort, unpublished
3. Interval debulking- Van driel 2018, NEJM- phase 3, stage 3 pts, 245 pts randomized to IDS with/without hipec. PFS 10.7 vs 14.2 mos. OS 33.9 vs 45.7 mos. No diff in grade 3 or 4 AE. (but 72% of HIPEC had colostomies, vs 43% in control)
   
   1. criticism: long accrual time 9 yrs- 3 pts per center per year, no bev or parp maintenance given, lack of stratification, diff of only 15 deaths between groups, PFS as primary endpoint, reduction of the number of patients (280 to 240 pts) needed to be randomized because of too slow accrual; much lower PFS (given 70% was R0) and OS in both arms than expected (expected: control PFS 18 mos, HIPEC PFS 24 mos) according to the statistical plan; the small size of the study, with imbalances between the 2 arms (eg,more low-grade tumors in the HIPEC arm, more high risk non serous in control group 13 vs 3 pts); the timing of randomization before the start of IDS; the lack of clear inclusion criteria for neoadjuvant chemotherapy; and the heterogeneity of the results, with the largest effect shown at the smaller centers (larger centers did not show any diff with HIPEC), questionable whether the adverse events were reported completely (only 16-19% had alopecia in both groups- not possible with taxol), median duration of surgery- hipec 338 vs 192 minutes
   2. Conclusion- further RCT needed to support this trial
4. Recurrent ovarian cancer
   
   1. • phase 2 Zivanovic 2020 JCO, 98 platinum sensitive, secondary debulking +/- HIPEC followed by adj chemo. Non significant- PFS 12.3 (HIPEC) vs 15.4 (non HIPEC). OS 53.1 mos (HIPEC) vs 69.2 (non hipec). Criticism- upfront setting, Used carbo- lacks synergistic mechanism with hyperthermia.
   2. Spiliotis 2015 Ann Surg Oncol, RCT phase 3= 120 women with secondary CRS +/- hipec. OS benefit in HIPEC 26.7 vs 13.4 mos. No diff in survival b/t platinum sens vs resistance

Question 53

Safety and quality of life with HIPEC?

Answer 53

1. Retrospective data 566 EOC patients who underwent HIPEC- morbidity of 31% and mortality of 0.8%
2. In other well selected patients- no diff between groups
3. Primary debulking with hipec, grade 3-4 morbidity 34% and postop death at 30 days was 0- recent meta-anaylsis
4. Acute renal failure with cisplatin in 40%- preventable by sodium thiosulfate which neutralizes cisplatin to protect renal function- prospective study showing no or decreased rates of renal failure with sodium thiosulfate
   
   1. sodium thiosulphate was administered at the start of perfusion as an in travenous bolus (9 g per square meter in 200 ml), followed by a continuous infusion (12 g per squaremeter in 1000 ml) over 6 hours. Urine production was maintained at a minimum of 1 ml per kilogram per hour during hyperthermic perfusion and for 3 hours after surgery.
5. Quality of life seems to be similar

Question 54

How did I treat ovarian carcinosarcoma? What data?

Answer 54

1. carbo/taxol x 6 cycles
2. Gog 261- Powell 2019 asco - noninferiority trial in uterine/ovarian CS - C/T vs PI. 637 pts accrued with a median follow-up of 61 months. The primary (U, n = 536) and secondary (O, n = 101) cohorts are analyzed separately and included 449 and 90 pts eligible pts, respectively.
3. O cohort (OS: PC 30mo vs PI 25mo; and PFS: 15 mo vs 10 respectively). Conclusions: PC was not inferior to PI for OS with longer PFS and similar QOL and neurotoxicity. These results establish a new standard regimen for women with CS

Question 56

Who gets consolidated. Asked for survival difference (PFS) in GOG 178. What dose of taxol was given and for how long?

Answer 56

1. GOG 178/Southwest Oncology Group (SWOG) 9701 demonstrated a significant increase in progression-free survival (PFS) for patients with advanced ovarian cancer in complete remission receiving 12 cycles compared to 3 cycles of monthly paclitaxel at 175 mg/m2 (modified later to 135 mg/m2) in a maintenance setting
2. no significant improvement in OS perhaps secondary to crossover effect or the fact that the control arm had 3 cycles of therapy instead of observation alone.

Question 57

What dose of carbo do I give. What is AUC. What is each axis on the AUC graph, how was this defined.

Answer 57

1. AUC is the “area under the curve” – a figure that reflects the concentration of drug in the body that doctors want to achieve
2. AUC is the total integrated area under the plasma drug concentration–time curve. It expresses the total amount of drug that comes into systemic circulation after administration of the drug.
3. Calvert formula- mg= auc x (GFR+25)

Question 58

What do I talk to pt about before starting chemo? Wanted me to say risk of secondary malignancies. Then he asked if patient developed leukemia, was there a test that would show it was chemo related…I vaguely remembered there was but I didn’t know details.

Answer 58

1. Receipt of chemotherapy was associated with a 1.5-fold to more than 10-fold higher risk of developing therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) for 22 types of solid tumors, a large-scale, population-based cohort study published in JAMA Oncology showed
2. MDS- mutations in hematopoietic stem cells, presence of one or more cytopenia, >10% of nucleated cells are morphologically dysplastic, <20% blasts forms in blood and bone marrow, and/or characteristic cytogenetic or molecular findings- without alternate cause of these findings
3. Presentation: cytopenia; anemia, infection, autoimmune abnormalities
4. Cbc- blood smear, bone marrow biopsy- increased blast but <20%, bone marrow aspirate

Question 59

Para-neoplastic syndrome. Wanted to know natural progression of disease, what was responsible for the syndrome. Treatment options available. How do you treat this patient and the likely outcomes.

Answer 59

1. Paraneoplastic syndromes are a group of rare disorders that are triggered by an abnormal immune system response to a cancerous tumor known as a “neoplasm.” Paraneoplastic syndromes are thought to happen when cancer-fighting antibodies or white blood cells (known as T cells) mistakenly attack normal cells in the nervous system. These disorders typically affect middle-aged to older people and are most common in individuals with lung, ovarian, lymphatic, or breast cancer. Neurologic symptoms generally develop over a period of days to weeks and usually occur prior to the tumor being discovered. These symptoms may include difficulty in walking or swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures, sensory loss in the limbs, and vertigo or dizziness.
2. There are no cures for paraneoplastic syndromes. There are no available treatments to stop progressive neurological damage. Generally, the stage of cancer at diagnosis determines the outcome.
3. When present, the tumor and cancer are treated first, followed by efforts to decrease the autoimmune response – either through steroids such as cortisone or prednisone, high-dose intravenous immunoglobulin, or irradiation. Plasmapheresis, a process that cleanses antibodies from the blood, may ease symptoms in people with paraneoplastic disorders that affect the peripheral nervous system. Speech and physical therapy may help individuals regain some functions.