GYN Monday update

Post by Jason A. Konner, MD:

Thinning crowds today betrayed increasing ASCO-weariness as the meeting draws near its close. The faithful came out this AM to the clinical science symposium to hear Dr. Audeh present results from the ICEBERG trial of a PARP(poly(ADP-ribose) polymerase-1) inhibitor, or PARPi*, called Olaparib in BRCA-deficient recurrent EOC. Yesterday at the breast plenary, another PARPi known as BSI-201, made a splash with data demonstrating improved clinical outcomes in triple-negative breast cancer when added to Gem/Carbo.
*The science, in brief: PARPi’s block Base Excision Repair of DNA. BRCA-deficient cancer cells already have impaired Homologous Repair of double stranded (DS) DNA breaks and the second hit by a PARPi leads to “synthetic lethality” from an abundance of DS breaks, preferentially in cancer cells, which are more prone to replication errors.
Response rates for Olaparib in EOC were high (33%) at 400 mg PO BID (less for 100 mg) in both plt-sens and resistant pts. Responses appeared better for BRCA2 mutated tumors and in resistant tumors, tho the numbers were small. Tox was mild (Gr ½ N/V/D, fatigue, abd pain). The 2nd talk presented a randomized phase 2 study of BIBF 1120, which targets VEGF, FGF, & PDGF, given to pts following a PR or CR to chemo for relapsed (<12 mo) dz. 5/43 (vs 0/40 placebo) pts appeared to have prolonged PFS and ph3 trials are warranted. Still, no standard mtnce therapy exists for EOC.
The afternoon brought a marathon poster discussion session, where abstracts were grouped as in the following summary (special thanks to Dr. William Tew for his help with these!):
1. Neoadjuvant chemo (NAC) in EOC:
a. To make a pre-op diagnosis, biopsy is best. Cytology of ascites is wrong 20% of time. Relying on CT and CA125 is also inferior
b. Best predictor for optimal debulking following NAC. . .drum-roll. . . it is not decline in CA-125, but rather: AGE!! (old=bad)
c. Do we need to do 6 (vs 3) cycles of NAC?? Answer: Stick with 3 for now.
d. Does length of interval between primary surgery and initiation of chemo matter? Answer: not in suboptimally debulked pts BUT delays may adversely affect outcomes of optimal patients.
2. MMMT (aka malignant mixed mullerian tumors, aka carcinosarcoma)
a. GOG study of tax/carbo in uterine MMMT: ORR 59% 1st line with 7 mo PFS and 14 mo OS. This lends strong support to using this regimen instead of cis or ifos-based regimens, which can be quite toxic for these poor-prognosis pts
b. 2 abstracts supported the use of adjuvant chemo, even for early stages, which I agree is appropriate. RT does not seem to improve survival
c. 1 study added 2 days of ifos to tax/carbo with good response rates at the cost of hi myelotox. Probably not worth it, since t/c alone achieves similar results.
3. Cervix
a. EGFR expression did not correlate with clinical outcomes
b. Oral TKI’s (pazopanib, lapatinib) may have some activity but more study is needed
c. Cetuximab can safely be added to cis/RT but no clear benefit
4. More EOC tales
a. German patients think that for follow-up: 1. CA-125 2. Vag Sono and 3. Pap are most important. Probably not too relevant here.
b. Dr. Chi made a 7-component nomogram for survival that needs to be validated
c. Salvage heated IP chemo can be done but is pretty toxic
5. There were a couple of interesting BRCA abstracts presented
6. BEV in EMC: RR is 13% in GOG study – not terrible! But more data are needed. . .. no perfs were seen 
My take on the day’s results : 1. The PARPi story is exciting and is bound to have a significant influence on the future treatment of EOC. There are several PARPi’s out there. Hopefully more trials will lead to approval soon. 2. I will tend to treat my new optimal EOC patients a bit earlier. 3. I will continue giving platinum-based adjuvant chemo for most MMMT’s, and, though ifos/Taxol remains the data-driven standard rx for patients with advanced MMMT, I will feel more comfortable substituting Taxol/Carbo when appropriate.

GYN Sunday update

Post by Jason A. Konner, MD:

Greetings from Orlando. After several quiet (and muggy) days, gyn has emerged noisily at ASCO, with an AM oral abstract session replete with practice-altering data, a controversial and compelling mid-day plenary talk regarding CA125 by Dr. Rustin himself, and a vast afternoon poster session with scattered tidbits of interest.

The AM session began with 2 studies reminding us that chemo-resistance and sensitivity assays, while chock full of emotional appeal and rationale, lack evidence of clinical benefit and retain their status as basically an expensive bad habit. Two studies, more suitable perhaps for a surgical conference, discussed SLN mapping in vulvar and cervical ca. The upshot is that SLN mapping appears safe for small (less than 4cm) squamous vulvar cancers and can now reasonably be offered by experienced surgeons. SLN mapping is not yet ready for cervical cancer outside of a clinical trial. Duenas-Gonzalez presented interesting data in 1st-line rx of cervical cancer. Gem/Cis/RT followed by BrachyRx followed by Adj.Gem/Cisx2 vs Cis/RT followed by BrachyRx for St IIB-IVA improved PFS and OS with HR=0.68. There were more than 500pts in 8 (largely non-western) countries. Unclear whether the Gem or the adjuvant Cis was responsible for the benefit (which correlated with systemic control), but any cervical trial with a survival benefit is notable. Confirmatory trials are needed before justifying the added toxicity (eg ANC and proctitis) of Gemzar. Pignata presented early results of MITO-2: upfront ovary rx with carbo/doxil (AUC5/30mg/m2Q3wk) vs carbo/taxol (AUC5/175mg/m2Q3wk). CT and CA125 response rates were similar but PFS data are still immature. Frequent rx delays with carbo/dox from heme tox, likely 2ry Q3wk schedule. Interesting but not as compelling as the CALYPSO study which used the same treatment arms (but with Q4wk C/Dox) and treated patients with platinum-sensitive recurrence. The non-inferiority EP was met, and there was even a suggestion of superiority. As expected, alopecia (7 v 84%) and neuropathy (4 vs 24%Gr2; 1 vs 4%Gr3) were lower for C/Dox, and interestingly hypersensitivity rxns to carbo were less (3 v.10%Gr2, 2 v.9%Gr3). HFS, mucositis, and CINV were more frequent but mild. PFS for carbo/doxil was 11.3 (v.9.4mo) with HR 0.82. Carbo/Doxil should join carbo/gem as a standard alternative to taxol/carbo for platinum-sens recurrent ov ca, especially if alopecia or neuropathy are concerns.

Rustin’s plenary trial demonstrated no survival advantage to treating recurrent ov ca based solely on CA125 w/o signs or symptoms. There is a strong patient and physician bias to closely following CA, but these data suggest that QOL is impaired by this practice, with no apparent benefit. I doubt many will cease measuring CA but I hope we will ease up on the frequency, and that we will be less compelled to “treat a number.” Not checking at all seems justifiable but hard to accept.

A quick rundown of the posters: weekly Topo does not work in ovary, IV bevacizumab can be combined with IP cis/taxol without too too much added toxicity (tho more trials are needed), a novel quinolone (of all things) and perhaps patupilone might be useful for ovary, better treatments for mucinous ov ca are needed, doublet therapy for platinum-resistant ov ca is not really beneficially, dose-dense (Q2wk) Taxol/carbo/gcsf is not feasible, 1st-line weekly Taxol is indeed less toxic than Q3wk but may not be more efficacious for ov ca (outside of Japan), and that angiogenesis in granulosa cell tumors is a bad thing, but avastin might possibly help. Well, there you have it.

Stay tuned for exciting data on PARPi’s in OvCa, and Avastin in endometrial coming tomorrow. . . .