OQ: Ovarian Cancer Recurrent Flashcards
For platinum sensitive ovarian cancer, would you do secondary cytoreductive surgery? What are studies for and against secondary cytoreductive surgery? When do you consider secondary debulking?
Plat sens recurrence:
Secondary cytoreductive surgery:
Salani (retrospective)
- inclusion >12mo from dx to recurrence, CR to primary tx, <5 recurrent sites
- # sites: OS 50 mo if 1-2 sites, 12mo if 3-5 sites
- residual dz: OS 50 mo if microscopic vs 7.2 mo if macroscopic residual
* ascites NOT associated with survival
Bristow – post recurrence survival associated with ability to get complete 2ndary cytoreduction.
MSKCC algorithm
GOG 213 (surgery was randomized, bev was randomized). 84% of pt’s received bev.
– surgery + chemo group vs. chemo only group
– no OS difference with trend favoring chemo only: 64.7 months chemo only vs 50.6 months surgery group;
– no PFS difference with trend favoring surgical group (18.9 surgery group vs 16.2 chemo only group).
- no selective criteria- physician decision
DESKTOP 1/2/3:
DESKTOP 1: proposed AGO score for prediction of complete cytoreduction
- OS 45 vs 19mo with complete resection
- predictors of complete resection: ECOG 0, no ascites > 500mL, no residual tumor at first surgery, stage 1-2 at initial dx
DESKTOP 2: Used score to help determine complete resection rate (complete resection rate was 75% if you use the score.
DESKTOP 3: platinum sensitive 6+ mos, positive AGO score then randomized to chemo vs. surgery plus chemo.
- AGO score (ECOG 0, ascites <500c, complete resection at initial surgery. Disease free interval >6 months)
- complete resection in 75% of patients.
- PFS 14 vs 18.4 mos (SS) favor surgery
- OS 46 vs 60.7mo (P=0.02) favor surgery if complete resection (R0)
- OS 46 vs 28.8mo favor chemo if incomplete resection
Ago score neg in 51% but 86% achieved CGR
Summary: (coleman’s distillation from SGO 2021)
SOC-1 (Lancet oncology 2021- china, secondary debulking- OS data not mature yet
- multicentre, open-label, randomised, controlled, phase 3 trial - 4 centers in China
- Eligibility- platinum-sensitive, potentially resectable disease according to the international model (iMODEL) score (SCORE <4.7) and PET-CT imaging (considered to be resectable by physician).
- iMODEL score - six variables: stage, residual disease after primary surgery, platinum-free interval, performance status, CA 125 at recurrence, and presence of ascites at recurrence. An iMODEL score of 4·7 or lower predicted a potentially complete resection. As per a protocol amendment, patients with an iMODEL score of more than 4·7 could only be included if the serum level of cancer antigen 125 was more than 105 U/mL, but the principal investigators assessed the disease to be resectable by PET-CT.
- Treatment: secondary cytoreductive surgery followed by intravenous chemotherapy (six 3-weekly cycles of intravenous paclitaxel [175 mg/m2] or docetaxel [75 mg/m2] combined with intravenous carboplatin AUC 5 MG/ML/MIN ; surgery group) or intravenous chemotherapy alone (no surgery group).
- Findings: 357 patients were recruited and randomly assigned to the surgery group (182) or the no surgery group (175; ITT population). Median follow-up was 36·0 months (IQR 18·1–58·3).
- . Median progression-free survival was 17·4 months (95% CI 15·0–19·8) in the surgery group and 11·9 months (10·0–13·8) in the no surgery group (hazard ratio [HR] 0·58; 95% CI 0·45–0·74; p<0·0001).
- median overall survival not mature- prelim 58·1 months (95% CI not estimable to not estimable) in the surgery group and 53·9 months (42·2–65·5) in the no surgery group (HR 0·82, 95% CI 0·57–1·19, NS)
- Interpretation: Secondary cytoreduction followed by chemotherapy was associated with significantly longer progression-free survival than was chemotherapy alone in patients with platinum-sensitive relapsed ovarian cancer
Consider secondary cytoreductive surgery if:
- Low-grade histology
- Limited disease (single site) amenable to R0
- meet desktop criteria
- DFI > 12 mo, shorter for select cases (Salani), although 213 and DESKTOP included 6mo platinum free
- ECOG 0
Why are desktop3 and GOG213 findings discordant?
- pt selection / inclusion criteria
- 213 includes all comers
- 213 use of bev (84% or pts) may distort benefit or lack of benefit of debulking
- different population - GOG213 had a lot of Asian patients (Japan, Korea)
- In GOG-0213, 84% of patients were given bevacizumab, compared to 23% in DESKTOP III (5% were given PARP inhibitor maintenance therapy), and the lowest rate of maintenance therapy was in SOC-1 (10%, most of which was PARP inhibitor therapy).
- The high use of maintenance therapy in GOG-0213 might partially explain the differences in outcomes between this trial and DESKTOP III.
Assuming you did the surgery (secondary debulking), what are your options for chemotherapy? Are there PFS or OS for these regimen? How do you decide between these options?
ICON 4: platinum/taxol vs conventional platinum based chemo (carbo alone, cytoxan/adria/cisplatin, carbo+cis, cis+adriamycin)
– PFS: 13mo vs 10mo (SS) favor platinum/taxol
– OS: 29mo vs 24 mo (SS) favor platinum/taxol
- banana signs for survival curves
GOG 213, second part evaluated bevacizumab
– chemo alone vs. chemo + bev; C/T vs. C/T/Bev + Bev until progression
PFS 14vs10 mos (SS)
– OS - there is a small, significant (questionable) benefit (played with stats): 37.3 months for chemo only vs 42.2 months for chemo + bev (5 months improvement)
AGO-OVAR 2.5 (Pfisterer/Plante): Carbo AUC5 vs. Carbo AUC4/Gem 1000, TFI >6mos
-PFS 6 vs. 8 (SS) favor carbo/gem, OS 18 mos (NS)
OCEANS carbo/gem vs carbo/gem/bev with bev maintenance
- PFS: CGB+B 12 vs 8 mo; HR 0.5 (SS)
- ORR: CGB+B 79 vs 57% (SS)
- OS: prelim NS ~34 mo
CALYPSO carbo AUC 5 taxol 175mg/m2 vs carbo AUC5 doxil (30mg/m2): noninferiority trial
– PFS 8.8mo carbo/taxol vs 9.4 carbo/doxil. Carbo/doxil less toxic
– OS 33 months carbo/taxol vs 30.7 mo carbo/doxil
Patient on Doxil/Avastin presents with abd pain, N/V…further management?
- work up for suspected bowel perforation and bowel obstruction
- CT abdomen / pelvis with IV and PO contrast
- if patient is stable and not septic for a leak - ok to manage with drain and abx (conservative management)
When do you use maintenance therapy with PARP inhibitor? How long do you continue the treatment?
- Olaparib, Nipariab, and Rucapairb all have FDA approval for this indication.
Study 19: platinum sensitive recurrence, 2+ platinum regimens with complete or partial response. Randomized to Olaparib 400 BID vs placebo
Essentially, improved PFS and OS in BRCA-mut and BRCA-wt, particularly in the former, OS was about 5 months and 3 months, respectively, with some having very long multi-year responses even in the BRCA-wt group.
SOLO 2: gBRCA, platinum sensitive HGSOC, >2 prior chemo. olaparib maintainance vs. placebo
- PFS 19 vs. 5mo (SS)
- published 3/2021: OS clinically better, but not statistically significant. p= 0.054, 95% CI includes 1.0!! HR 0.7, 38.8 vs 51.7mo → median OS improved by 12.9 months with maintenance olaparib vs placebo.
NOVA: platinum sensitive, >2 prior chemo. Niraparib vs. placebo
- gBRCA: PFS 21 vs 5(SS)
- nonBRCA but HRD+: PFS 12.9 vs 3.8mo (SS)
- HRD neg: PFS 6.9 vs 3.8m (SS)
Ariel3: platinum sensitive HGSOC or endometrioid. 1+ prior chemo. rucaparib 600 BID vs placebo
s/gBRCA vs wt-LOH high vs wt-LOH low - PFS 12.8vs vs 5.7 v 5.2mo, significant improvements it turns out, so that’s why it’s approved.
JCO review 2019 on platinum sensitive ovarian cancer
NCCN guideline (2021)
What are the PARP inhibitors approved for monotherapy in the recurrent setting?
Olaparib if germline BRCA after 3 or more lines (Study 42)
Audeh: gBRCA, olaparib 400BID vs 100 BID, any recurrent ovarian cancer
- ORR 30% (plat resistant), 38% (plat sensitive) at higher dose.
- ORR 13% at lower dose
Study 42: Phase II study of olaparib in gBRCA. Plat sensitive or resistant.
- ORR 34%, median duration 7.9mo (plat sensitive RR 46%; plat resistant RR 30%)
- no diff in duration of response based on platinum sensitivity
- Rucaparib if germline or somatic BRCA after 2 or more lines (FDA approval based on pooled analysis of ARIEL2 and study 10)*
ARIEL2: Rucaparib as treatment of disease after > 2 prior platinums, normal CA125.
- HRD was assessed by Foundation Medicine assay. Percentage of genomic LOH >=14% = LOH high
- Part 1: received at least 1 prior platinum-based regimen and were considered platinum-sensitive
- Part 2: 3 or 4 prior chemotherapy regimens. They could be platinum-sensitive, platinum-resistant, or platinum-refractory
- Part 1: median DoR 5.7 months, PFS: 12.8 mo (BRCA mut) vs 5.7 mo (LOH-hi) vs 5.2 mo (LOH-low). PFS was sig longer in BRCA mut (HR 0.27) and LOH hi (HR 0.62)compared to LOH low subgroup.
- g/sBRCA: PFS 16.6 vs 5mo (SS)
- HRD: 13.6 vs 5.4mo (SS)
- all comers: 10.8 vs 5.4m (SS)
Study 10 (Kristeleit et al)
- phase 1-2 dose escalation of rucaparib
- Phase 2: platinum sensitive recurrent ov ca, gBRCA1/2, after 2-4 prior lines therapy, >= 6 mo after prior platinum based therapy
- ORR 59.5%.
Integrated analysis of data from study 10 + ARIEL2 (Oza, Gyn Onc 2017)
- Population - g/s BRCA mutation, >= 2 prior lines chemo, platinum sensitive/resistant/refractory
- ORR 53.5%, CR 8.5%, PR 45.3%, median DoR 9.2 months
- Niraparib if BRCA germline/somatic or HRD after 3 or more lines of chemotherapy*
***HRD positive status defined by 1) deleterious BRCA mutation or 2) genomic instability and who have progressed > 6 months after response to the last platinum based chemotherapy.
QUADRA: niraparib after 3 prior lines of chemo (incl platinum resistant) (phase 2, single arm)
- 37/463 with prior PARPi exposure (excluded from analysis)
- BRCAm, platinum sensitive ORR 39%
- BRCAm, platinum resistant/refractory: ORR 27%
- HRD+, PARPi naive: ORR 28%, DoR 9.2m, PFS 5.5m
- HRD+, platinum sensitive ORR 26%
- HRD+, platinum resistant/refractory ORR 10%
- niraparib is active with ORR 28%
What are the chemotherapy options for platinum resistant ovarian cancer?
AURELIA
– single agent chemo alone vs same + bev: PFS 3.4mo vs 6.7 mo with bev
– single agent taxol superior with OS benefit
Pt on Doxil/bev for platinum-resistant recurrence. Showed a plain abd X-ray of colon obstruction. CT showing diffuse carcinomatosis, SBO w/o transition point. Colonic obstruction, how to manage.
Symptomatic management, NGT, IVF, anti-emetics, octreotide, steroids (I forgot this one), palliative (G-tube or colonic stent), what else (not sure if they were trying to get me to say TPN but I didn’t open that can of worms). How to manage pain from obstruction.
Recurrent ovarian cancer with LBO, gets a colonic stent, obstruction resolves but now she’s constipated from opioids, how do you manage.
- bowel regimen.
- Methylnaltrexone- An opioid receptor antagonist which blocks opioid binding at the mu receptor, methylnaltrexone is a quaternary derivative of naltrexone with restricted ability to cross the blood-brain barrier. It therefore functions as a peripheral acting opioid antagonist, including actions on the gastrointestinal tract to inhibit opioid-induced decreased gastrointestinal motility and delay in gastrointestinal transit time, thereby decreasing opioid-induced constipation. Does not affect opioid analgesic effects.
Palliative care for obstruction, how to counsel pts.
G tube for palliation. Intestinal bypass surgery. Stenting. Cecostomy.
55 y.o. undergoing Doxil chemotherapy for recurrent ovarian cancer develops palmar/plantar erythodysesthesia. Describe pharmacokinetics, toxicity, and management
Doxil – greater than 90% of the drug is encapsulated in liposome carriers which are phospholipid bilayers
Pharmacokinetics: longer plasma ½ life (45 vs 9 hrs) , slower plasma clearance, reduced volume of dist compared to doxorubicin. Tumor tissue concentrations are increased by 4 to 16 fold.
Toxicity:
- Minimal cardiotoxicity/not a vesicant
- acute infusion reactions – occurs in 5-10% of patients - flushing, dyspnea, swelling of face, headache, back pain, tightness in chest and throat, hypotension, usually with the first treatment
- Myelosuppression - dose limiting toxicity with leukopenia more common than thrombocytopenia or anemia
- Nausea / vomiting
- Mucositis and diarrhea (common but not dose limiting)
- Hand-foot syndrome / palmar plantar erythrodysesthesia / PPE: skin rash, swelling erythema, pain, desquamation – occurs in 26% if 50/m2 given Q4wks
- Hyperpigmentation of nails, skin rash, urticaria
- Alopecia 15%
- Red-orange discoloration of urine
Admin – infusion should be given at an initial rate of 1 mg/min over a period of at least 30 minutes to avoid the risk of infusion-associated reaction. This is thought to be related to the lipid component of liposomal doxorubicin.
Tx for PPE grade 3:
- Delay up to 2 wks until resolved, then 25% dose reduction
- Pain: analgesics or topical anesthetics (lidocaine patches)
- Inflammation: topical high-potency corticosteroids
- Hyperkeratosis: topical keratolytics (??? Urea based lotion))
- Erosions: petroleum/lanolin-based ointments
- Other°: oral vitamin B6 (Pyridoxine) 400 mg, oral vitamin E, topical 99% dimethylsulfoxide (DMSO), topical sildenafil, oral corticosteroids
