Bevacizumab and Intravenous or Intraperitoneal Chemotherapy in Treating Patients With Stage II, Stage III, or Stage IV Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

Dear Dr. Goodman,

My mother has just undergone surgery for Stage IIB ovarian cancer. She is now being recommended for the "Bevacizumab and Intravenous or Intraperitoneal Chemotherapy in Treating Patients With Stage II, Stage III, or Stage IV Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer"
trial by her surgical oncologist.  We are trying to assist her in deciding whether to take part in the study, and I hope you might be able to answer a few questions for us.
-What are the advantages of using 'Bev' (Avastin)?  What are the risks?
-Should she consider IP chemo even if she does not take part in this trial?  Is that possible?  
-Do you think the advantages of IP chemo outweigh the risks?
-Would you recommend the multi-drug approach of the trial, or would you suggest a single-drug regime would be preferable?
I realize it may be hard to comment without knowing more about my mother's particular circumstances, but any light you can shed on the above areas of concern would be very much appreciated.
Thank you.
Holly

[Annekathryn Goodman, M.D.]

Dear Holly,
thank you for your question
and JR - thank you for your excellent comments

clinical trials serve the purpose of asking and then hopefully answering the question: is the new therapy better than current standard of care?

to rigorously answer that question, we try to recruit people to participate in a study where they are randomly assigned the standard of care or the study drug . That is called a phase 3 randomized trial

it takes many years and many compromises in terms of trial design to get an answer.and sometimes disappointingly, the answer is not so helpful. or the study drug is not better than standard of care.

one of the questions you should ask the doctors recommending this trial is : what is the question being answered? is it : is IV or IP chemo better when bevicizumab is added?
is there a comparison in this trial to chemo without bev?


here is our current knowledge based on phase 3 trials:
IP chemo (with cisplatin and taxol ) in women with optimally surgically cytoreduced stage III ovarian cancer prolongs survival compared to IV cisplatin and taxol

the addition of bev to carbo and taxol does not seem to change remission rates but giving bev for 12 month after completion the 6 cycles of IV taxol and carbo does imporve survival by about 3.7 months


here are my notes from the recent ASCO meeting where the bevicizumab trial was presented:
OS means overall survival
PFS is progression free survival
QOL quality of life

Robert Burger surg onc Fox Chase GOG 218 : Rob thanked the patients AND their significant others – very poignant
Stage 3  randomized , double trial ov , fallopian, peritoneal cancer upfront bevicizimab
Protocol:
Stratified by prognostic  factors
Stage III and IV
Surgery 12 weeks prior to enrolled
Performance status >2
Optimal or Suboptimal (2/3rds suboptimal) in each group
arm I : Taxol 175mg.m2  carbo  IV AUC 6 6 cycles plus placebo maintenance 16 cycles
arm II : Taxol/ carbo /bev 15mg/kg (initiated cycle2) 6 cycles plus placebo maintenance  16 cycles
arm III: taxol/carbo/bev  6 cycles   plus maintenance with bev   16 cycles
22 cycles of therapy for each group

Primary analysis – PFS
Secondary analysis – OS, QOL,  Adverse effects
Statistics: adequately powered to  90%

1873 patients enrolled  2005-2009, initially they excluded optimal  debulked patients because of a competing study but then changed halfway through to include optimal l

ARM I  PFS 10.3 mos  ( CA 125 censored :12 mos)
ARM II PFS   11
ARM III PFS 14.1 mos  (CA 125 censored :18 mos)  (significant) hazard ratio 0.71

Concerned over bev affecting CA 125 levels
I OS 39 mos
II OS 39 mos
III OS 39 mos

Follow up 17.4 months

42 -48 % stopped due to disease progression in I and II ,  arm III 26% discontinued
GI perforation doubled in arms  II and III but less than 3%
HTN 23% greater in II and III
Proteinuria less than 2% but significantly increase in II and III
No other difference in adverse events

Prognostic factors: Stage, age, Performance Status

Outstanding analysis by Dr Elizabeth Eisenberg: issues:

-in consolidation trials, need to look at overall survival and not PFS.That data is not mature for GOG 218
- Strong trial with few weaknesses from design standpoint.

-no separate arm of bev only for maintenance with carbo/taxol alone
-how does using CA 125 for response data alter our judgment of results?
-is there is linear relationship between PFS and OS for anti-angiogenesis factors-extraordinary increase in cost of 200,000 dollars per patient
-is a 3.7 month increase in disease free interval meaningful?

And my question: why was drop out from disease progression so much higher in arms  I and II.   Compared to arm III. did this bias results?

[jr1971]

Holly

I am not a doctor but I am aware of similar trial - My wife does not qualify for these trials as she has already been through first line treatment with Paclitaxel/Carboplatin. One of the leads in the UK for the Avastin trials happens to be my wife's doctor and he talked us through the treatment options - she is having Avastin but not as part of a trial.

Avastin is a drug that helps prevent the formation of new blood vessels to tumours. This, while not offering a cure, should help to limit growth and prevent/delay recurrence. It can cause side effects such as bowel perforation so they tend to delay the start of treatment after any bowel related surgery - in fact they also recommend delaying treatment for some weeks after any surgery as the drug can affect healing of new surgical scars. The other side effects can be high blood pressure - this can be controlled with other drugs. These side effects don't affect everyone. The benefits seem to be good in terms of preventing and delaying recurrence vs chemo without Avastin. Results from recent trials seem to suggest that the benefits could be significant.

I don't know much about IP chemo so I will leave that to the experts.

Jon