PET scans have become well established in initial staging of lung cancer and many other cancers, but another setting in which they may emerge as useful is in assessing response to treatment. Some oncologists and patients are already doing this, but the standard test most commonly used for measuring response is the CT scan, which is widely available and has the benefit of years and years of experience. We grade our work in oncology by looking for tumor shrinkage. The percentage of patients who have an “objective response” of tumor shrinkage by 50% is one of our key endpoints when we describe a treatment for cancer, but we now know that it is definitely very possible to have patients live longer without having major tumor shrinkage. Cancer without any treatment is definitely going to grow, so even keeping it stable in size can appropriately be considered a relative improvement. I’ll describe the evidence showing survival benefit in the setting of stable disease in a dedicated post soon.
But the issue here is the concept that either before a CT scan is able to detect changes in size, or in the event that there is no obvious change in the size of a cancer mass on CT, the PET scan may detect decreased or increased metabolic activity that can help us determine whether the treatment is helpful or futile. Even if nobody wants to learn that a treatment is ineffective, if it is causing side effects without the real promise of benefit, it makes sense to abandon that futile treatment earlier rather than later. And now that we have a growing number of treatments available for advanced NSCLC, we might consider it increasingly important to not waste our time, strength, and money on treatments that aren’t going to provide a benefit. A trial published in 2003 by Weber and colleagues out of Germany (abstract here) evaluated 57 patients with advanced NSCLC who received standard chemotherapy after initial PET scan evaluation and then another PET scan after just one cycle of therapy. They defined a “response” by PET as a greater than 20% reduction in the “standard uptake value”, a measurement of how metabolically active the tumor was in taking up radiolabeled sugar molecules. Not surprisingly, responses by PET were significantly associated with responses that were later determined by CT scans. And survival was remarkably better for patients who responded by PET after a single cycle of chemo:
(click to enlarge)
In fact, the median (the half way point, half above and half below) progression-free survival was three times longer in PET responders than in PET non-responders (163 vs. 54 days), and the median overall survival was also significantly longer for PET responders (252 vs. 151 days).
Subsequent trials have demonstrated similar results. A trial from Korea was presented at our large international oncology meeting, ASCO, in 2006 (abstract here), describing the experience with PET scans done on 31 patients with advanced NSCLC who had a PET/CT fusion scan before and after a single cycle of treatment. This treatment was combination chemotherapy for 26, and single-agent Iressa, the EGFR inhibitor, for 5. PET response, again defined as a 20% or greater decline in SUV of the primary tumor, was very highly associated with best response to treatment as measured by CT. More importantly, the median time to progression on that treatment was four times longer in the PET responders (10.1 vs. 2.6 months).
Moving assessment of therapy even sooner, another abstract at ASCO 2006 by Sohn and colleagues looked at a new (and not generally available) type of PET can known as FLT (for[18F]fluorothymidine, so let’s just say FLT), just 1 day before and 3 days after starting Iressa at 250 mg daily. This was in a trial of 22 never-smokers with advanced adenocarcinoma NSCLC. As I’ve mentioned in prior posts, never-smokers have a high likelihood of responding to EGFR tyrosine kinase inhibitors (particularly Asian patients, as in this Korean trial). Twelve of the 22 patients (54%) had a significant response. The investigators were able to predict later CT responses by this novel PET technology even 3 days into treatment.
Three days…wow. Now there are a few cautionary points I’d make. There have been some very quick and profound responses to drugs like Iressa and Tarceva that have occurred within days, and sometimes just by watching patients get better practically in front of your eyes or on an x-ray (most commonly described with bronchioloalveolar carcinoma (BAC)), but we don’t really expect to see dramatic results from chemo over days. We use a 6-9 week period to check our results by CT most commonly because otherwise it can be like watching grass grow, so even if there are changes, we can’t see the differences if we monitor too quickly. PET scans may offer an opportunity for earlier feedback. The trials that have shown this are still pretty small, and follow-up PET scans for advanced NSCLC are not routinely done in clinical practice, including mine. While an early PET scan may help us determine that some patients are showing early progression, or an early response, I wouldn’t want to abandon a modestly effective treatment too early. Unfortunately, the tumors that aren’t responding well to a first treatment often don’t respond to later ones. So a real downside to peeking early, especially when we don’t have a lot of experience and evidence to justify it yet, is that we might give patients a much earlier opportunity to discover that treatment isn’t doing working as we’d hoped. This is a field that is changing quickly, and we always have to be careful not to have our fancy new tools run far ahead of our understanding of how best to use them. We have many goals in treating lung cancer, and hope is an all too limited resource.
posted by Dr. West @ 7:29 pm link to this post
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January 12th, 2007 at 12:11 pm
Dr. West -
You’ve hit a very pertinent nail right on the head. Sometimes all the fancy tests in the world can be as much bad as good.
Having survived 3 years as a stage IV neversmoker (initially with mets to spine, shoulder and mediastinal nodes) I have been PET scanned nearly each time an assessment scan was needed, my local oncologists mantra being that more information is good information. This strategy has yielded results at times helpful and at times amazingly confounding.
A Pet/CT fusion scan in 2005 that seemed to indicate an all out jailbreak of disease in my bones (and moderate SUV increase in the primary lung tumor and nodes), yet no evidence on CT of measurable progression. A full spinal MRI seemed to indicate some disease progression in the bone.The decision was made to abandon the Iressa I’d been on for over a year (with and after initial taxol/carbo in 2004) based on the PET and get in a trial of the then phase 1 trial of HKI-272.
I was tested for the “Iressa” EGFR mutation in the interim just to prove I had it (given the great Iressa response I had) and to qualify for the trial.
No mutations found. No trial.
In the interim 2 mos without treatment while awaiting all this trial qualification stuff, I began a regimen of high dose Celebrex (400mg, 2x daily) based on early work with it at UCLA (a trial has since seemed to indicate celebrex with Tarceva provided a 3x better response rate than tarceva alone). To be sure the disease wasn’t running amuck in this long waiting period another PET/CT (6 weeks after the one that prompted all this panic) was done. Same machine, same radiologist throughout the whole process. PET results showed NO activity in bones, stable in lung and nodes. A response to Celebrex alone?
In spite of evidence to the contrary that I would not respond to Tarceva (garnered from the mutation testing flunk-out) I decided to give Tarceva a whirl anyway.
Another PET/CT was done (now 6 weeks since the last one) 5 days after the first tarceva pill was taken (still on Celebrex then as well). Results? All bones quiet, lung and lymphs’ SUV’s down by 30% or more. A wizbang response!
Stayed on Tarceva and Celebrex fror nearly a year until a PET/CT in late May 2006 indicated disease progression. CT confirmed it.
Went on Avastin/Alimta (stopped Celebrex) with good response in soft issue disease and stability in all bone save an advancing sacrel met.
Dec 2006 PET/CT (on a new F18-FDG super scanner; Pet & CT all in one connected tube; took only 20 minutes to do the glide). Results were a Christmas tree of activity. New, old and who knows what stage of disease. BUT the confusion began when the CT showed no measurable growth anywhere and SUV values for the lung and nodes actually fell by 50% in 3 months into the 2 - 3 range. Existing bony lesions were all stable in size and SUV uptake. Apparent new bony disease spots measured at most at 2. Lots of head scratching ensued. New PET/CT “extra” sensitive? Avastin working on soft tissue but not well enough alone on bones? My “norm” for PET uptake different than accepted standards?
It was decided that since I had such an extensive record of scans, it was an opportunity to do some real sleuthing into this diagnostic quagmire.
A bone scan showed nothing. Zilch. Nada. Hmmm . . .
An MRI of the entire spine and pelvic region showed lesions - some old, some maybe new. Only confirmed growth from MRI on that pesky sacral tumor we had been watching.
So, after consultations with lung oncs from near and far it came down to whether I had any bone pain (none) and “how did I feel”? The answer there was fine.
So-o-o, we’re rolling the dice again, sticking with Avastin alone and adding back Tarceva (with Celebrex). 4+ weeks finds me feeling better than ever, dealing with a Tarceva rash (which appeared 5 days after the first pill) and approaching Feb., when a scan will need to be done to assess things.
Just what kind of scan you ask? Tempted to do the PET/CT on the new fangled machine again just out of curiosity to see what it thinks is going on this time.
So, for me PET has helped nip things in the bud at certain times and caused undo testing and treatment changes at others, adding fuel to your fire about how sometimes all this information is great, but just what does it really mean?
Tom C
January 12th, 2007 at 5:04 pm
Tom,
That’s an amazing history! It’s great to hear that you’re doing so well, after all of those curves in the road.
You also raise the issue of celebrex (celecoxib), which has had a huge amount of buzz around it, but the evidence behind it has been up and down. Unfortunately, on the internet, raising questions about celebrex as a cancer treatment feels like you’re criticizing motherhood and apple pie.
I’ve been somewhat skeptical , the impressive UCLA results notwithstanding (a small trial), but cases like yours and a few others I know of are at least removing some of my skepticism and making me reconsider the potential benefits. I’d really like to see more data from good trials, but I’m scratching my head again as I wonder how much of your impressive results might be from tarceva, from celebrex, or maybe the combination is the key. I wish we heard more stories like yours.
-Dr. West
January 13th, 2007 at 8:57 am
Dr. West,
I just wanted to share what I think is a positive note about using a PET/CT fusion scan. The report stated I had “a new focus of incresed activity in the region of left adnexa which has an SUVmax of 7.9. There is no discrete mass seen in the area on the CT image.” Follow up ultrasound did find a mass that turned out to be mets to the ovary. It was removed and confirmed as lung cancer mets. I think this indicates that the PET picked up the problem and that the CT did not. I am 18 months post diagnosis with stage IV disease and believe that I am doing well primarily as the result of being able to identify and respond quickly to the ever changing course of the disease, as well as my oncologist’s willingness to treat me aggressively. I do appreciate all the information you provide. At some point would give us your opinion on the Internation Lung Cancer Action Screening Project? Thanks again, Myrtle
January 13th, 2007 at 9:21 am
Myrtle,
Yes, PET scans are very good at detecting occult metastatic disease. The problem is when they’re so sensitive that they pick up things that turn out to be inflammation or infection, but you had to go through several extra tests and sometimes a surgery to learn it wasn’t cancer. You can’t get sensitivity without its evil twin of over-sensitivity and “false positives” (things that were considered worrisome on a scan that turn out to be nothing).
It’s fitting that you bring up the Early Lung Cancer Action Project (ELCAP) for screening, because there’s similar dilemmas of CTs being sensitive but maybe too sensitive in that setting, similar to the questions with PET here. I’ve been meaning to write about screening but frankly have been dragging my feet on that. This is because it’s so complex and a topic that tends to get people quite emotional, but it’s hard for me discuss the pros and cons without upsetting people. Whether we’re talking about doctors, patients, family members, or whoever, people tend to approach the screening issue as an “us” vs. “them” polarized view and often seem unwilling to consider the counterpoints against their view as something other than a personal affront. I promise to get to it in the next week or two, but covering screening in a balanced way feels like you’re going to try to mediate peace in the Middle East.
-Dr. West
January 13th, 2007 at 11:00 am
Dr. West,
I really had not thought about it that way. I was anxious to find out if the activity was lung cancer or a new primary ovarian cancer. To me the sooner we had the answer, the better. Would there have been any other way to determine that? Also I did want to add that we watched the growth for six weeks via ultrasound before proceeding with the surgery.
I am so interested to read your perspective on the (ELCAP). I have made it a project of mine to push, prod, drag people to participate in the trial because I feel that if it had been available to me, it may have save my life. I know that you do not let a little controversy stop you and I for one am anxious to understand all the negatives.
January 13th, 2007 at 12:39 pm
Myrtle,
I’ll also add that there’s no controversy at all about having people participate on the ELCAP trial. That’s terrific.
I appreciate your perspective, and I have also treated patients who have had their cancers detected by screening on the ELCAP trial. I promise to tackle it and try to open up a good discussion on the subject.
-Dr. West