Resistance of Iressa? - 1267996

Hello Hong,

Welcome to GRACE. I'm sorry to hear of your mom's diagnosis and the recent increase in her symptoms. Since her scans apparently do not show evidence of progression in the lung or elsewhere, the increase in her pleural effusion would not necessarily be reliable evidence that Iressa has ceased to be effective. Effusions can wax and wane, sometimes not as the result of progression. As Dr. West has said:

"The effusion, whether increasing or decreasing, is a “soft endpoint” that really doesn’t say anything conclusive about the status of the cancer. His weight loss and weakness are more concerning, and it’s possible that this could represent progressing disease, or at least clinical worsening, but the clearest indicator of progression is evidence of clear progression of a measurable aspect of the cancer or a new area of disease. Presumably, there isn’t much progression if the scan doesn’t show any appreciable change, though it’s possible for everything to be obscured by the scarring in the pleural space." - http://cancergrace.org/topic/nsclc-mpe-pleurodesis-failed-inspira-pleur…

Your mom's symptoms of cough, shortness of breath and fatigue can all be due to an increasing pleural effusion. Her recent symptoms would be more concerning and certainly something to discuss with her oncologist.

Tumor markers do not tend to be an accurate measure of the status of lung cancer, as describe in this GRACE FAQ: http://cancergrace.org/cancer-101/2010/09/16/cancer-101-faq-assessment-…

For legal and practical reasons, no one on this site can tell you or your mom what she should do with regard to her current treatment. She would need to discuss her situation with her own doctor, who knows her case best.

JimC
Forum moderator

Hi Hong, Welcome to Grace, I’m very sorry for your mom's terrible problems.
I just wanted to add a few posts from Dr. Harman a palliative care specialist at Stanford and one of Grace's greatest advocates and contributors.

I hope they help,
Janine

http://cancergrace.org/cancer-treatments/2009/05/09/managing-cough/
http://cancergrace.org/cancer-treatments/2012/08/03/dr-stephanie-harman…
http://cancergrace.org/cancer-treatments/2012/08/09/dr-harman-depressio…

Jim and Janine have covered the main highlights, but I'll highlight a few key points:

1) Both the recurrence of pleural fluid and rising serum tumor markers suggest some degree of progression, but if you cannot see any evidence of measurable disease progressing, most experts (including myself) would not consider this to represent clinically significant progression. Patients on targeted therapies can often continue to do very well for months, and up to 20% of patients in one retrospective review of cases at Dana Farber Cancer Institute with limited progression were able to go a year or longer before they showed enough progression to justify a change in systemic therapy.

In other words, most experts would favor holding steady and not making rash changes based on the earliest suggestive evidence for progression, especially serum tumor markers, which have no validated role in making clinical decisions, and I believe they are more likely to lead to bad decisions than good ones if made without evidence of significant imaging changes (not just 1-2 mm of barely perceptible progression).

2) In the absence of clinically significant progression, it is very appropriate to continue the same targeted therapy.

3) One clinically significant progression is established, there are at least two 3rd generation EGFR inhibitors, rociletinib and AZD9291, that have been shown to have significant activity against EGFR mutation positive patients with acquired resistance (progression after a good initial response) to Iresssa (gefitinib) or Tarceva (erlotinib) or Gilotrif (afatinib) if they have a T790M mutation -- this is a mutation that is found in 60% of patients with acquired resistance. There are multiple clinical trials with these agents now being conducted around the world, and we hope one or both will become commercially available in the next year or so. Otherwise, standard chemotherapy is most commonly given and can be very helpful.

-Dr. West

Dr. West had this to say in a prior post, “Practically speaking, a leading option in someone developing acquired resistance would be to repeat a biopsy of a progressing lesion and look for the T790M mutation. If it is present, either of the third generation EGFR TKIs in wide testing, AZD9291 or rociletinib (CO-1686), have very promising activity and are being tested in several very large trials. However, it would be exceptionally difficult to try to biopsy a 3 mm nodule. One very reasonable approach would be to wait until there is an area of progression big enough to biopsy before pursuing a change.
Finally, chemotherapy remains a reasonable option after progression on an EGFR TKI. After years of only being able to speculate about whether we should continue the EGFR TKI after starting chemotherapy, the IMPRESS trial recently demonstrated no improvement in progression-free survival and a strong trend toward worse overall survival in the patients who continued EGFR TKI with concurrent chemotherapy compared with the patients who stopped EGFR TKI and went on to chemo alone. So most experts would now favor discontinuing the EGFR TKI when a decision is made to start chemotherapy.” http://cancergrace.org/topic/tarceva-resitance/#post-1267910

The best way to know for sure about trials is to speak with the trialist’s offices themselves. Your mom’s onc should be able to help.

continued,

The best way to know for sure about trials is to speak with the trialist’s offices themselves. Your mom’s onc should be able to help.

Studying AZD9291 in China. Though the page states “not yet recruiting” it would be worth checking to see if that’s changed. It takes place in Guangzhou, China
https://clinicaltrials.gov/ct2/show/NCT02151981?term=AZD9291&cond=nsclc…

Studying rociletinib (CO-1686) I didn’t find any trials testing CO1686 in China though there are sometimes mistakes. I’ll continue to look around on the link below to see if there’s anything at least close.
https://clinicaltrials.gov/ct2/results?term=CO-1686&recr=&rslt=&type=&c…

I'm very sorry your mom has progressed. I wonder if she plans to stay on treatment until just before starting a new one. Waiting until the last few days helps negate the possible so called flare caused by a tki keeping the cancer from growing faster. Another thought you didn't asked but I'll say, my husband and I have discussed the possibility of travel for treatment and he is the such a homebody that I'm not sure he'd do it because being home outweighs not. Of course not everybody is like my husband and many much prefer to travel for more options but it is a conversation I hope she has.

All the Best,
Janine

It sounds like her progression is in the range that I would definitely consider clinically significant. She has acquired resistance. The available evidence is that most older patients can feasibly receive and benefit from chemotherapy -- I would have to defer to the doctors evaluating her directly about whether she could tolerate it. Otherwise, while the third generation EGFR inhibitors are an attractive option, they are only available in trials, most of which are specifically for patients who have a biopsy that shows a T790M mutation.

Beyond that, I don't have any additional evidence-based recommendations beyond those that are already covered.

Good luck.

-Dr. West

Most oncologists now favor stopping Iressa in this type of situation. As Janine stated earlier in this thread, quoting Dr. West:

"After years of only being able to speculate about whether we should continue the EGFR TKI after starting chemotherapy, the IMPRESS trial recently demonstrated no improvement in progression-free survival and a strong trend toward worse overall survival in the patients who continued EGFR TKI with concurrent chemotherapy compared with the patients who stopped EGFR TKI and went on to chemo alone. So most experts would now favor discontinuing the EGFR TKI when a decision is made to start chemotherapy.” http://cancergrace.org/topic/tarceva-resitance/#post-1267910

There is a long-running debate among oncologists over the relative value of cisplatin and carboplatin. It's not so much a question of whether cisplatin is better, but how much better considering it is often more difficult for patients. Dr. West wrote an entire post on this subject, stating:

"My perspective has been that I do recommend carboplatin-based chemo for the majority of my patients in the advanced disease setting, where cisplatin can’t increase the cure rate, and the differences in efficacy are relatively small and, from my vantage point, offset by the often problematic toxicity of cisplatin, and that with the vast majority of my patients receiving later treatments, the differences in first-line treatment shoudl be smaller still." - http://cancergrace.org/lung/2007/08/19/cis-vs-carbo-for-adv-nsclc/

As far as brain metastases, it seems that you indicated that at the time of diagnosis in May 2014, a brain scan was clear. Many oncologists, including the GRACE faculty, do not normally order follow-up brain scans in the absence of concerning symptoms, as the evidence does not show improved survival versus scanning when symptoms develop.

JimC
Forum moderator

Jim provided great thoughts here. Cisplatin is well known for causing nausea and vomiting. The best way to clarify whether it's likely to be from treatment or the disease, which is certainly another reason for a patient to feel poorly and experience nausea/vomiting, it makes sense to hold chemo and see whether the symptoms improve or not. If so, that argues that chemo is the likely culprit. If not, we become more concerned that disease progression is a more likely cause and would be inclined to repeat imaging to clarify.

Good luck.

-Dr. West

There are definitely special needs for those being treated for lung cancer who are rather frail. It is more common to treat with just one non platinum drug if the doublet is too toxic than to lower the dose of a doublet. Below is a link to a podcast on the subject of treating those who are frail. We also have other info on the subject. A good start would be to follow the links under the podcast window. http://cancergrace.org/lung/2010/05/15/adv-nsclc-in-poor-risk-hesketh-k…

Yes, ceritinib brand name Zykadia is a drug recently approved for people with ALK mutation in nsclc. We have tons of info on the subject should your mom prove to have this mutation.

Dr. West answered the question about loculated pleural effusions this way, “The main way I know is to use ultrasound guidance to isolate where the effusion is, then place the needle right there. That’s usually something that needs to be done by more specialized people than the oncologist, like the people who work for interventional radiology or a pulmonologist who does a lot of thoracenteses (the procedure to remove pleural fluid collections). The other alternative is to have a surgeon go into the chest cavity and break up the adhesions that are causing the loculated fluid collections. Often, when a surgeon does that, they would do a pleurodesis (procedure to cause deliberate scarring to close off that space between the outside of the lung and the inside of the chest wall).” http://cancergrace.org/topic/loculated-pleura-effusion

All the best,
Janine

Hong, you're mom is so lucky to have you as her advocate. Obviously we all agree on that or we wouldn't be on Grace. The real exciting thing is that we have so many brilliant and busy oncologists on our team who want their patients and patients' caregivers to be as educated as possible so they can be active members of treatment plans.

Your thread like all others is for everyone who reads Grace not just for those who brave writing the questions. With that in mind it would be most helpful to start a new thread when you have a new question. You wouldn't need to start 3 new threads for your last post but you could start a new thread with a title something like Lung Cancer Complications or anything that would give others an idea about what the thread is about. That way someone could find this info easily through a search.

Too, we plan on you and your mom being around for a while so you could write a signature in your Grace profile (found by clicking on your user name hcui0313 next to any of your posts. In the signature space write a short history like those of others on Grace, mine just below all my posts. That way those who comment will have quick access to the needed context and you wouldn't have to rewrite every time.

By no means should you take this as anything but info to help everyone. This is all new for all of us. We all understand the incredible stress whether as a loved one or a person with this awful disease. So take this for what it is. Making our world an easier place. :)

Sincerely,
Janine

Low dose chemotherapy is a very appropriate choice, and many, probably nearly all lung cancer experts recognize that patients who are elderly and frail may well be best served by lower dose chemotherapy and that if pateints are not well enough to tolerate chemotherapy well, full dose chemo absolutely may make people very ill and shorten survival. There is also a point when patients are not likely to benefit from any further anti-cancer therapy and may well be harmed by it.

Accordingly, I must mention that radiation to the chest does not have any anticipated survival benefit in patients with stage IV disease, even if it can be useful for patients coughing up blood, with painful metastases that can be shrunk with radiation to improve pain control, or given to shrink a cancer that is very bulky and blocking an airway. But doing radiation to the chest just because a patient is too frail for chemotherapy would not be expected to improve outcomes in any way, except to treat symptoms in the specific symptoms I mention above.

Here is a good summary of the management of recurrent pleural effusions:

http://cancergrace.org/lung/2007/03/18/mpe-managment-options/

Finally, while ceritinib would be a good treatment for a patient found to have an ALK rearrangement, that is not likely at all in someone who is already known to have an activating EGFR mutation. Not to say that it never happens that you see an EGFR mutation and ALK rearrangement in the same patient, but it would be extremely rare.

Good luck.

-Dr. West