Mets Day 524: Dose Dense MVAC Q&A

In the past few days I have exchanged a number of emails with Drs. Apolo and Aragon-Ching, and this morning I had a follow-up phone consultation with Dr. Apolo, on whether to proceed with dose dense (dd) MVAC chemotherapy.  Following are my questions and their answers:  

Q&A with Dr. Aragon-Ching of George Washington University:

Aragon-Ching Question 1:  Dr. Apolo said that she was going to have my cancer sequenced.  Could that data provide any insight into whether dose dense MVAC (or perhaps a future clinical trial) might be appropriate for me?
 Aragon-Ching Answer 1:   I would defer to Dr. Apolo.

Aragon-Ching Question 2:  You told me that you could not identify any data comparing median overall survival of patients with mets BC who do not have dose dense chemo to those who do.  Where could I find data on those who do not have any treatment?
Aragon-Ching Answer 2:  One phase III trial comparing a salvage chemotherapy drug called vinflunine (not approved in the US, this was mainly a European trial) was compared to what we call best supportive care (no chemo) and the median overall survival was a little over 4 months (link here)

Aragon-Ching Question 3:  The PET scan showed there was questionable focal uptake in the right medial hepatic lobe.  Does the possibility of metastatic activity in the liver support going forward with dose dense chemo, or is it irrelevant because it is indeterminate?   
Aragon-Ching Answer 3:  The presence of known visceral disease is an adverse prognostic factor, compared to just adenopathy alone ... it would support treatment with chemotherapy.

Aragon-Ching Question 4:  The 2001 study that you gave me (http://www.ncbi.nlm.nih.gov/pubmed/11352955) paradoxically showed that patients receiving dose dense MVAC had a somewhat higher response rate (62% to 50%) and two year survival rate (35% vs. 25%) than patients receiving regular MVAC, but that there was no statistical difference in either the overall survival rate, or time to progression of further metastases.  I'm having a hard time understanding these data.  Can you shed some insight on it?  Also, that study was of patients who had not previously received platinum-based therapy, so it seems less applicable to me.  Am I misreading it?
Aragon-Ching Answer 4:  You are absolutely right in reading this...this was a neoadjuvant trial in patients never been treated with chemo (so this is not technically applicable to you) but I wanted to give you an idea of what the regimen contained & its schedule (dose dense) and it was being compared to the standard dose MVAC.  Having said this, patients who undergo dose dense MVAC who have been previously treated may in fact develop more toxicities than what this paper is discussing.

Aragon-Ching Question 5:  The 2012 study (http://www.ncbi.nlm.nih.gov/pubmed/22364733) found there was a 61% response rate, with 10% having a complete response.  Digging deeper into the data, it appears that the positive rates are skewed by the inclusion of patients who did not have distant metastatic disease: three of the four patients who had a complete response did not have metastatic disease.  For those with distant metastases, the median time to progression was 4.4 months, and median overall survival was 5.7 months.  These don't sound very encouraging to me.  Am I missing something? 
Aragon-Ching Answer 5:  This trial included all patients with metastatic sites of disease but made no distinction whether they were distant sites or not.

Q&A with Dr. Apolo of NIH's National Cancer Institute:


Apolo Question 1:  Dr. Aragon-Ching said that, if I was to proceed with dose dense MVAC, it could disqualify me from later clinical trials.  You and I had discussed several possible trials; would any of those be closed off if I proceeded?
 Apolo Answer 1:  You would still be eligible for my clinical trials if you have proceed with MVAC.

Apolo Question 2:  Even if those trial were foreclosed to me, would you still recommend my proceeding with dose dense MVAC?
 Apolo Answer 2:   Yes, but they are not

Apolo Question 3: You said that you were going to have my cancer sequenced.  Has that happened yet, and if so, does that data provide any insights of what kind of therapy or trial might be the most appropriate for me?
Apolo Answer 3:  I will follow up on the sequencing on Thursday when I meet with our pathologist. This may make a differences what you receive after chemo but the panel is only 50 genes, so the findings are limited.  Foundation medicine has a panel with 200 genes and I think insurance
covers this. I am not sure if I can send this out from the NCI because we don’t deal with insurance but maybe Dr. Aragon-Ching can, I will ask her.

Apolo Question 4:  Can you point me to data showing median overall survival of patients with mets BC who do not have dose dense chemo?
Apolo Answer 4:  I have attached some pivotal papers on first line chemotherapy for metastatic disease. Including the phase 3 of (gemcitabine and cisplatin) GC vs MVAC (link here) and the PCG (paclitaxel/gem/cis) vs GC (link here). I have also including a retrospective report from France on patients that received ddMVAC after GC (link here).

Apolo Question 5:  The PET scan showed there was questionable focal uptake in the right medial hepatic lobe.  Does the possibility of metastatic activity in the liver support going forward with dose dense chemo, or is it irrelevant because it is indeterminate?
Apolo Answer 5:  If you do have disease in the liver then ddMVAC would not be the best choice of therapy because my goal is to have you achieve a complete response (CR) with the ddMVAC. The chances that you achieve a CR are highest with lymph node disease and low with liver disease. Chemotherapy in your setting is given for palliation but you don’t have symptoms, this is Dr. Plimack's reservation. My goal is to a achieve a CR which is generally achieved in 5% of patients with GC and 20% with ddMVAC when it is given as the first chemotherapy to patients with metastatic disease. You would be given ddMVAC as your second chemotherapy BUT first in the metastatic setting. The French studied showed a CR rate of 10% with ddMVAC (in your setting). Patients that achieve a complete response have longer survivals. That being said ddMVAC has a lot of side effects and is hard to get through.  I highly respect Dr. Steinberg but he is a urologist not a medical oncologist. I consulted your case with Dr. Cora Sternberg the oncologist who developed ddMVAC (I attached her original publication from 2001) (link here) and she completely agrees with me.

 Apolo Question 6.  Your email notes that ddMVAC would not be the best choice if I have liver disease.  Given the ambiguous results from the PET scan, does it make sense to try to rule that out before embarking on ddMVAC?  How would I go about doing that?
Apolo Answer 6:  The PET scan is inconclusive.  It's very had to tell from a PET scan whether there is metastatic activity in the liver, because the entire liver is hot.  We use CT scans to tell whether there is node enlargement or tumors in the liver.  The PET scan suggests that, if there was metastatic activity in your liver, it is not in the lymph nodes, but within your liver.  If a subsequent CT scan showed a tumor in the liver, then you should not proceed with ddMVAC, or you should stop it if it was started. 

Apolo Question 7:  Thank you for consulting with Dr. Cora Sternberg, who developed the 2001 study.  As I read it, that study has a paradox.  On the one hand, it showed that patients receiving ddMVAC had a somewhat higher response rate (62% to 50%) and two year survival rate (35% vs. 25%) than patients receiving regular MVAC, but on the other hand, it showed that there was no statistically significant difference in either the overall survival rate, or time to progression of further metastases.  I'm having a hard time reconciling these data, especially as they may apply to my situation.  Does this suggest that there is a better chance that ddMVAC may provide a complete response (CR) or partial response (PR) while I have the chemo, but once the distant tumors develop, the disease moves faster, so my OS will be similar?  Also, that study was of patients who had not previously received platinum-based therapy; as we know, I failed GemCis, so I'm wondering how applicable that data is to me.
Apolo Answer 7:  The study does have that paradox, and we struggle with the data.  The studies suggest that the rates of CR are significantly higher with ddMVAC than with regular MVAC or GC chemo, especially perioperatively.  These data support ddMVAC as a second line therapy.  There has never been a phase III clinical trial comparing GC to ddMVAC.  We are starting that now.  The data suggest that median progression-free survival for ddMVAC is 9.1 months, with regular MVAC it is 8.2 months, with GC it is 7.4 months, and with no therapy, about 5.5 months.  Extrapolating from the studies, ddMVAC gives you your best chance of CR or PR.
   
Apolo Question 8:  The 2012 French retrospective study appears to divide patients into two groups:  adjuvant chemo and metastatic disease.  While it found there was a 61% response rate with ddMVAC, with 10% having a complete response, it appears that the best results were obtained by patients who had adjuvant chemo but did not did not have distant metastatic disease. For those with distant metastases, the median time to progression was 4.4 months, and median overall survival was 5.7 months.  Am I correct to put myself into the mets group, and anticipate a lower likelihood of CR or PR?
Apolo Answer 8:  You are between the two groups.  You had positive nodes after your surgery, but it has not spread systemically, and you had no distant tumors.  Looking at your cancer from the lymph node that we biopsied under the microscope, it was poorly differentiated, and very aggressive.  It did not have many of the characteristics of micropappillary bladder cancer.  Instead, it looked like a tumor that will grow quickly.  It does not look like a cancer that will be indolent, meaning that it will grow slowly.  

 Apolo Question 9:  The 2012 taxanes study is provocative.  Is adding a taxane into ddMVAC an option?  Is there any downside to trying it?
Apolo Answer 9: Taxanes with ddMVAC is too toxic and is not an option. 

Apolo Question 10:  Boiling everything down, I'm trying to decide whether 3 months of
feeling lousy while having ddMVAC is going to be worth it.  If it adds 3 months of life to the back end, but I lose three months while going through the chemo, then it seems to be a wash, and probably not worth it.  If there is a reasonable prospect of getting a complete response and substantially adding more time, then it becomes more attractive. But if it's going to permanently weaken my immune system and compromise my remaining time with little likelihood of success, then I'd rather not do it.  Do you agree with how I've boiled it down?
Apolo Answer 10:  It's a fair way of looking at it.  You may get 3 months or more on the back end, or you may not.  Don't pay too much attention to the French retrospective study on toxicities, because we have learned so much on how to minimize the toxicities.  I give 3 liters of hydration with the MVAC, so it can take up to 9 hours to receive the full chemo dose -- 6 hours for hydration, 3 hours for the drugs.  I usually keep patients overnight unless they live very close by.  Many of my patients tolerate ddMVAC very well.  Most recently, I gave 5 rounds of ddMVAC to a nurse who works at the NCI hospital.  She kept working while having each round, except for round 5, when she developed mouth sores and could not eat.  Another recent patient lived on a farm and continued to work as a farmer while having the chemo.  Each patient is different.  The most common side effects are mouth sores, fatigue, and fever.  You are relatively young and otherwise healthy, so you should be able to tolerate the ddMVAC well. 

Apolo Question 11:  I understand that, on balance, you believe that the pros substantially outweigh the cons, that I'll get through ddMVAC, and have a fair chance at either CR or PR for some period of time.  I'm unclear from the literature how long the CR or PR typically lasts.  It appears that, for some, it's just while the chemo is being administered, and once it stops, the disease comes back like gangbusters.  For a minority of other patients, it appears that the response extends beyond the period of treatment.  Is it fair to say that, in my case, there is no way of knowing whether I'll have any favorable response, but that you believe that having ddMVAC is the best way to extend my life while still maintaining a decent quality of life?
Apolo Answer 11:  I would suggest proceeding with ddMVAC with Dr. Aragon-Ching. You do
not need to get restaged with Dr. Plimack, I can do it or Dr. Aragon-Ching can do it. Treating you with ddMVAC is the most aggressive option.  If it were me in you shoes, I'd do ddMVAC.  If you decide not proceed with the chemotherapy that's OK too, it really it is a personal choice.