Lung Cancer / Mesothelioma
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Loading ...A couple of weeks ago I described in a prior post the design and general results of a trial coded as JMEN by the sponsor company, Eli Lilly. This study randomized patients to either maintenance/early second line alimta (pemetrexed) or a placebo after four cycles of initial platinum-based doublet chemo with a drug other than alimta. The randomization was only for the patients who didn’t progress after the first four cycles of chemo, and as described in the prior post, there was a very highly statistically significant improvement in progression-free survival with maintenance alimta, and while the overall survival benefit wasn’t quite statistically significant, it was a very respectable difference of nearly three months (9 vs. 12 months) that was arguably quite clinically signficant and was associated with a “p-value” of 0.06 (meaning there was only a 6% chance that the difference could be by chance alone, while the standard cut-off we use is a p-value of 0.05, or a 5% or less probability of a difference being by chance alone) .
Combined with the results from a pretty similar trial of immediate vs. delayed second-line treatment with taxotere (docetaxel) that was presented at the ASCO meeting last year (see prior post), we now have two recent large studies that show major improvements in progression-free survival and a nearly significant improvement in overall survival. Taken together, these results are arguably enough to change our standard approach to moving second line treatment to right after first line, effectively blurring the edges so that non-progressing patients transition straight to maintenance therapy after 4 cycles of first line chemo (or possibly 6 as a variant that wasn’t used in these two trials, but you’d likely have many patients show progression between the 4th and 6th cycles).
If you believe this, there are still several open questions for which we just don’t have evidence to help provide an answer. For example, it’s standard to give patients on first line chemo/avastin (bevacizumab) maintenance avastin alone after 4-6 cycles with the chemo. Should these patients now switch to alimta with avastin, or taxotere with avastin, as a new combination maintenance therapy? These combinations have been studied in small trials, but they aren’t a standard approach at this time. The same issue of potentially overlapping maintenance strategies applies to the EGFR monoclonal antibody erbitux (cetuximab) if we consider the results of the recent FLEX trial to be worthy of making erbitux a standard of care for first line treatment, perhaps in avastin-ineligible patients or in other some other patients. We don’t yet have any study results published that have reported the combinations of alimta or taxotere with erbitux, but there are large studies being done that are using these combinations.
Another question is whether maintenance tarceva (EGFR oral inhibitor erlotinib) after 4-6 cycles of initial first line chemo is a good idea. We don’t have reported data on the issue of starting tarceva immediately after first line chemo in nonprogressing patients, but this research is being completed, and I suspect we may see results by next year. If positive, we’ll again be thinking about various options that could include early/immediate second line chemo or tarceva, just as we have those options as “delayed” second line treatment that usually starts when a patient has shown progression. And tarceva could also be combined with avastin potentially as a maintenance strategy in avastin-eligible patients, as this combination has already been studied and has looked encouraging in a few trials (see prior post). We have very little data on tarceva with erbitux, but they’ve been combined in some small studies as well.
BUT there were plenty of skeptics at the ASCO meeting, and their concerns centered around one rather critical design flaw in the trial. That flaw is that the trial wasn’t of immediate vs. delayed alimta, but rather that the arm of the trial that received placebo instead of alimta didn’t necessarily get treated with alimta or anything else after progression. In fact, similar to the shortcoming from the taxotere trial of immediate vs. delayed second line chemo presented last year, many patients didn’t receive any further treatment after progressing, so this alimta trial was partly a study of the patients on immediate maintenance alimta getting more opportunity for effective therapy than the patients on the placebo arm. In fact, 50% of the patients on the placebo arm received no additional chemo, and only 11% received alimta, with many others receiving agents without an established role in previously treated patients. This issue is a serious flaw in the trial, but my overall assessment is that the results suggest that immediate second line treatment also provides a greater opportunity for patients to get effective treatments and do better over time.
I wouldn’t say that immediate transition to second line chemo is a clear standard that oncologists would be wrong not to pursue, but I’m likely to change my practice now to be much more inclined to offer and recommend maintenance chemo and believe the standard is now shifting. It’s certainly still very appropriate to give a break to a patient who needs or just wants one, but I would say that the imperfect evidence supports the concept that survival is maximized by having patients on treatment for as much time as feasible, at least for the first 2-3 lines of therapy. And in someone who wants or needs a break, I’d be inclined to restart treatment within a month or two, as soon as they’re up for it, rather than wait until they are definitely feeling worse from the effects of progressing cancer.
And while we don’t have evidence yet with tarceva, I think it would be quite reasonable and tempting to substitute early/maintenance tarceva for chemo for patients with a minimal or no smoking history or with a known EGFR mutation, etc. But that will be a much stronger consideration once we see results from the ongoing studies looking at this.
One other significant issue that is worth noting is the JMEN trial of maintenance alimta showed a benefit that was only seen in patients with non-squamous tumors. This result really bolsters the idea put forth on the basis of another alimta trial (see prior post) that suggested that alimta is a significantly more effective agent for patients with adenocarcinomas and non-squamous NSCLC tumors compared with squamous tumors. We’ll cover this issue more in the next post.
Posted in: Chemotherapy, Core Concepts, Lung Cancer, Metastatic/Recurrent NSCLC, Second Line and Later, Non-Small Cell Lung Cancer (NSCLC), Second-line treatment, Stage IV/Advanced/Metastatic NSCLC, Treatment
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Dr. West:
Just what options are left–if any–for those of us who have squamous cell carcinoma?
Carole
My “signature” didn’t show up. For more details re my tx to date, see My Story at Lungevity:
http://lungevity.org/l_community/viewtopic.php?t=36841
In brief: NSCLC Poorly differentiated squamous cell carcinoma dx 01/07 (5 cm. tumor and right hilar and mediastinum sub-carina lymph node involvement); Tx: concurrent cisplatin/etoposide and 3D conformational radiation (30 of 33 tx); docetaxel (1 of 3); tx halted due to radiation pneumonitis and pulmonary embolism. 01/08-04/08 Tarceva (didn’t work); 05-06/08 2 Alimta infusions, strong toxicity).
Carole
Plenty of things, like taxanes, cis- or carbo-platin, gemcitabine, navelbine, etc. are all perfectly good for squamous cancer and may even work better — we really haven’t tested these drugs by histology carefully. In terms of new therapies, a class of drugs called IGF-1R inhibitors may work especially well for patients with squamous cancers, but these are still investigational (I’ve written a bit on this topic and will write an update soon from a recent ASCO presentation). Patients with squamous cancers are becoming a recognized unmet need that will get greater attention in clinical trials now.
-Dr. West
I finished my first line of treatment for stage IV adenocarcinoma in February and have had no tx since then. My last chest ct shows no evidence of disease. I am interested in your comment about survival being maximized by patients being on treatment for as much time as feasible. Would you consider this prudent in the face of no evidence of (measurable) disease? I see my Onc In August, do you think I should I talk to him about “mainenance” with alimta? (I am an “ex”smoker) Last visit he said he felt it would be better to wait until progression was detectable. While I really understand,and don’t have an objection to, this approach, I have so enjoyed this “cancer free” few months,,,would like to see it continue as long as possible.
Terryl
Thanks for your response, Dr. West. Very much appreciated.
Carole
Terryl,
Actually, the setting of no evidence of disease or a very indolent cancer is a setting where I would feel most comfortable with not pursuing any maintenance and would probably recommend against it for my own patients in this kind of situation. I think what the evidence suggests most is that it’s helpful to get started on a next line of therapy before the patient has declined to the point of “missing the boat” on a next course of treatment, basically becoming too ill to safely pursue more treatment. I think following patients more closely and jumping in well before they miss the opportunity to start a next line of treatment would lead to similarly favorable outcomes, and I think that the patients with minimal bulk of disease and especially no evidence of disease would have the best chance of having progression detected far before the window closes on safe, effective subsequent treatment.
-Dr. West
Dr. West
My first posting here, so I have a few questions and some background.
My husband, an otherwise fit and healthy 41 year old never-smoker was diagnosed with adenocarcinoma Stage IIIB (with one tumor, pleural effusion and some nodes, including one a bit lower, but not on other side of chest - “medial” or something - showing on the CT scan, but no brain mets) in January 2008. We were informed it is “incurable” and that neither radiation nor surgery were reasonable courses of treatment. The tumor was hotdog shaped ~ about 6 cm at longest measurement. He has been on a weekly taxol/carboplatin cocktail with Avastin every 3rd week since mid-January, and today is scheduled for probably his last - the 20th infusion. He has tolerated and responded well- the first CT after treatment showing 90% reduction in volume (now more like a pencil) and all the fluid gone. The 2nd CT after tx (about 6 weeks ago) showing minimal improvement (but some) from that- Dr. said it might even just be scar tissue at that point. So, he will have a CT scan next week to determine whether any change has occurred since last CT- if no further reduction, no more Taxol/Carboplatin, but Dr. plans to continue with Avastin and start Tarceva.
Questions:
He has had more than the 6 cycles already, should there even be any consideration of further chemo- even if we see further reduction? It seems there is a limit to effectiveness of chemo- even if the patient is tolerating it.
Does this seem the best “maintenance” or “early second line” treatment? Should we consider Alimta? Something else?
Should/could radiation be a possibility? Our Dr. did say that if there is no progression in a year, he might think outside the box and consider radiation. Should we wait a year?
If CT shows progression, what are the options for treatment?
I saw a phase III trial for “stimuvax” that looked really interesting. What do you think of these kind of vaccine therapies?
Thanks for your help,
Sarah
sarahmac
Sarah,
We just don’t know of an optimal maintenance therapy, and I really doubt that there is a best choice for all patients. I have no enthusiasm at all about continuing platinum-based doublet chemo on someone beyond 6 cycles, except if someone is still showing tumor shrinkage between the 4th and 6th cycles, which is very rare. Continuing maintenance avastin alone is a fine idea, with some evidence to support it, and there’s also evidence to support chemo without avastin, as I describe above. I think either avastin alone, chemo alone (and alimta’s a very fine choice in a patients with non-squamous cancer), or avastin/chemo are all very appropriate options — avastin with alimta, taxotere, or tarceva have all been studied and appear pretty safe and encouraging. For a never-smoker, tarceva would rise to the top of my list, even though we don’t have firm evidence for it as a maintenance therapy yet — that work is still being completed. So I think tarceva/avastin would be a strong consideration, but there are many.
If the effusion showed cancer cells (a malignant pleural effusion), it’s really not conventionally considered curable and is treated the same as stage IV disease, for which adding radiation doesn’t add a significant survival benefit overall. I think it’s reasonable to recognize that individual cases are appropriate to consider individually, so I’d advocate an approach of “never say never”, but I’d really favor waiting a long enough time to really know whether this will declare itself as multifocal in the next several months. The longer the period of time that passes without any evidence of disease elsewhere, the more reasonable the idea would be of pursuing some local treatment like radiation. And again, I’m presuming that there was good reason to think this was really advanced lung cancer and not “dry IIIB” NSCLC, which is potentially curable with aggressive chemo and radiation.
The Stimuvax approach has looked encouraging as a follow-up after chemo and radiation for stage IIIB, locally advanced but potentially curable NSCLC, but it doesn’t appear to add anything for patients with advanced disease, which would include stage IV (frankly metastatic) and also “wet IIIB” NSCLC.
-Dr. West
Dr. West,
thanks for your comprehensive response- yes the pleural effusion was malignant. It was a very sudden onset, went from one day running hills to the next with sudden pain in the ribs and shortness of breath, diagnosis was within 2 weeks of that date. I guess I keep hoping that maybe the effusion with cancer cells was there only such a short time that it isn’t REALLY REALLY “wet IIIB” as you term it.
Again thank you for clarifying that indeed this next stage is less than completely clear. Sometimes that seems the scariest thing of all- well, after the diagnosis itself. I will speak with the Dr about Alimta as a potential next treatment. Might he be holding onto that as a secondline treatment, for when/if there is a progression?
As I’m sure you can imagine, this has been one heck of an education and we’re still grappling with comprehending things.
Sarah
sarahmac
I admit that the term “wet IIIB” is rather inelegant, but it’s the term that nearly all oncologists use to describe a lung cancer with a malignant pleural effusion, I’m sure because it’s much shorter and easier to say.
In the interest of full disclosure to you and others who read here, I’ll need to add that I’m just coming back from an international lung cancer meeting where people have had the chance to discuss this trial about early second line or “maintenance” alimta, and I’m surprised by ho many people are unconvinced or even skeptical. They generally point to the fact that only 50% of the patients on htis trial received any further therapy, and that’s a valid concern that makes this trial a bit too much of a test of more treatment vs. less treatment overall. But they also point to the overall survival with a p-value of 0.06 as if it’s as simple as a black and white answer of statistical significance at 0.05 or not. I think that’s foolish, especially with the previous trial with taxotere showing a remarkably similar result (after which the lung community said that we need more evidence, which we’re now discounting).
Regardless, it’s not clear that a shift to immediate second line treatment with alimta or taxotere is going to take the world by storm, but I still think the evidence does support not waiting too long. Still, it’s a controversial point.
-Dr. West
Dr. West, Thanks for all your posts, they are really informative and helpful.
We are actually using the early maintenance treatment with Alimta, Well, it is not quite “maintenance” yet, we just finished three cycles, disease is stable, but I do have some doubts on whether to keep using Alimta until progression.
My Mom, 55 years old Asian, never smoked, was diagnosed with Stage IV Adenocarcinoma early this year, with no obvious bone mets or brain mets found in recent checkups. After completing 4 cycles of docetaxel (Taxotere) + Cisplatin chemo, where first two cycles delivered a partial release and last two kept a stable disease, we immediately use single agent Alimta as second line chemo. After two cycles of Alimta injection, we had a stable disease. She is in good shape, and seems tolerating chemos well.
Now I am quite worried about what to do next. I believe Iressa is going to work for my mom (even we haven’t done the EGFR mutation test because of the scarce of originally obtained tissue). We will definitely try it after Alimta.
My concerns are, shall we use Alimta as a “maintenance” treatment until progression, or just do 4 or 6 cycles and wait for progression? If the response to treatment is SD, would those maintenance injections after standard 6-cycle treatment significantly increase progression-free period?
To make it more complicated, can we adjust the Alimta maintenance interim to a longer period, e.g. one month, 42 days, or even two month?
I discovered an interesting case in another lung cancer forum I visited frequently. A 67 Asian female never-smoker with Stage IV Adenocarcinoma started her treatment with Iressa. After becoming resistant to it, she received Alimta as a maintenance treatment. Her first couple of injections of Alimta were on schedule, the first day of every 21 days. But considering economic and patient’s emotional stress, they delayed injections to one month, sometimes 40 days, or even two months. Now she has received 8 Alimta treatments in about 10 months. Although there is no obvious tumor shrinkage, CEA declined from 300 sth. to about 4, chest CT and brain MRI both showed stable.
Can you recall any trails where they decide optimal Alimta dosage and treatment schedule? I guess those would be Phase II trails. Is there any findings might favorite longer interim for Alimta maintenance? And finally, back to Iressa, is there any trails support that we start Iressa right after 4 or 6 cycles of Alima?
Sorry for all these questions. I truly appreciate your response and discussion.
Ming
Ming,
I don’t think there are any trial results to guide these decisions.
It has not been my practice to extend the time between alimta treatments beyond three weeks. As a general philosophy, if a significant response doesn’t appear likely to be achieved but someone remains stable, I am very much in favor of giving as little treatment as necessary to maintain stability. While I have had patients in whom I’ve done dose reductions, I don’t think I’ve had occasion to increase the interval between treatments, at least on a regular basis. I think it’s reasonable if a patient is showing no evidence of progression, by scans, tumor markers, etc., to prolong that interval as one option. In the event of a symptom like fatigue or just a patient’s desire for time off, I have suggested that patients take a break from chemo for a while and continued to monitor them carefully, then restarted chemo (generally the same chemo at a time of subsequent progression). This is all on the basis of style and clinical judgment rather than clinical trial results telling us how to proceed. After first line treatment with platinum-based doublets, I’ve been reluctant to stop a treatment before a patient shows evidence of progression, so I don’t stop after 4 or 6 or even 10-12 cycles if they are tolerating it well and not progressing.
I am definitely optimistic about the likelihood of benefit from an EGFR inhibitor in a never-smoking Asian female (although I am currently treating a very young never-smoking Chinese woman who just progressed immediately and rapidly through tarceva, so it’s not a certainty). But I doubt it would make any significant difference whether it’s started very soon or at another time in the future when a patient has the same performance status. What little evidence we have suggests that patients who are destined to have a great benefit from iressa or tarceva will get it whenever they receive the drug, whether first line or second line or later.
-Dr. West
Thanks for your credible response, Dr. West. It definitly helps us to make an informed decision. Truly appreciated.
Ming
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