Lung Cancer / Mesothelioma
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Loading ...As I mentioned in prior posts on the topic of second-line therapy, taxotere was the first treatment approved for second-line treatment of NSCLC. Back in 2000, first-line chemo with platinum-based doublets was becoming increasingly established as demonstrating a consistent survival benefit of several months for previously untreated patients with advanced NSCLC, and then a couple of trials came out that demonstrated a modest survival benefit that for second-line taxotere, compared to either supportive care alone or compared to alternative chemotherapy (navelbine or ifosfamide). However, even after these trials demonstrated a survival benefit and taxotere was approved by the FDA for treatment as second-line therapy, only a minority of patients were getting treated in this way. A large part of this was the concern about the challenging side effects of treatment with taxotere every three weeks. Although taxotere is clearly among the most active and effective agents available for treatment of NSCLC (and many other cancers), it can cause a lot of fatigue and decreased blood counts and other problematic adverse effects. Over the last few years, the alternative approach of Alimta (also known as pemetrexed) has become available and approved by the FDA for second-line treatment of NSCLC, and it is being studied in more and more treatment settings as a potentially appealing option in lung cancer.
Alimta, or pemetrexed, is a form of standard chemotherapy that is a newer version of old standard chemo like methotrexate. These drugs are called antifolates, and they inhibit the production of critical components of DNA that growing cells need to survive. Because cancer cells are growing faster than other cells, they are particularly susceptible to the damaging effects of antifolates and can lead to death of cancer cells. The “MTA” at the end of the name Alimta stands for multi-targeted antifolate, because, as its name suggests, it actually has several targets that are critical in DNA and protein formation (too complicated and not interesting enough to go into here). In truth, the distinctions between what is called standard chemotherapy and “targeted therapy” are actually not very clear. Even regular chemo is targeted, but we have generally had a better idea of the target for the newer molecular therapies.
Alimta was approved by the FDA in 2003 for the treatment of malignant pleural mesothelioma, a cancer of the lining around the lung that has been notoriously difficult to treat. In combination with cisplatin, alimta was associated with a clear improvement in survival, as well as a much better response rate and improvements in breathing capacity, compared with cisplatin alone (abstract here). It was also found during that early international trial that patients receiving Alimta did clearly better, with much less of a drop in blood counts and no decrease in efficacy (perhaps even an improvement), when vitamin B12 and folate were given to patients along with alimta. Since then, starting patients on B12 and folate before starting alimta has become the standard approach.
Alimta was tested in NSCLC in a large trial with nearly 600 patients treated in the second-line setting. In this trial, reported by Hanna and colleagues (abstract here), both of these drugs were given by vein one day every three weeks, and each was given along with decadron, a steroid, for a few days around the time of chemo in order to minimize acute side effects, most notably the risk of a hypersensitivity (allergic) reaction. The trial breakdown was as shown here:
(click to enlarge)
The trial was remarkable for how similarly the two drugs worked. In fact, they both had the same modest response rate (but consistent for the best we’ve been able to do in second-line) of 9%, with another 46% for each treatment achieving stable disease:
They also had the same progression-free survival of 2.9 months for each group, the exact same overall survival at one year of 29.7% (identical down to a tenth of a percent), and a median overall survival of 8 months on both arms:
The results of the two arms are so similar that it’s hard to even see that there are two curves. So they had the same activity, and a quality of life analysis showed no significant differences in quality of life. However, there were differences that favored alimta in terms of several side effects. The patients receiving alimta were significantly less likely to have a serious drop in white blood cells (also known as neutropenia, which is associated with increased risk of infections), neutropenia with fevers, or infections even without low blood counts. They were also significantly less likely to require support with growth factors like G-CSF (neupogen), or, quite importantly, to need to be hospitalized for fevers with low blood counts (which generally requires patients to come into the hospital for IV antibiotics) or to be hospitalized for any cause. Although the impression I and many other oncologists get is that patients tend to tolerate alimta more favorably overall, the other side effects on this trial were not significantly different between the taxotere and the alimta arms. Regardless, with such limited treatment options available for previously treated patients with advanced NSCLC, and with one more active agent with an apparently more favorable side effect profile (although with a higher risk of abnormal liver tests on alimta and a small risk of developing a rash), the FDA approved alimta for second-line treatment in 2004.
Since that time, alimta has been widely used in this setting and also increasingly in other aspects of lung cancer. In the US, it is now used more commonly as second-line treatment than taxotere, because many patients have tolerated it very well, and it is given over 10 minutes every three weeks, which is a very convenient schedule for many people. It isn’t asscociated with hair loss either, which is a nice feature for many patients. There are still plenty of patients who complain of significant fatigue and other side effects on it, but considering its activity, it often has a very favorable therapeutic ratio, the balance of efficacy vs. side effects. And since it has proven its value in previously treated lung cancer and in mesothelioma, two very high bars to show benefit, I expect that it will also prove itself to be a very active and useful drug in other settings of lung cancer and oncology in general in the coming years. The research is ongoing, and I”ll share results as they become available.
Posted in: Chemotherapy, Lung Cancer, Non-Small Cell Lung Cancer (NSCLC), Second-line treatment, Stage IV/Advanced/Metastatic NSCLC, Treatment
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This is less optimistic (side effects and efficacy)regarding Alimta than I had expected, after reading earlier reports. Would you agree that Tarceva, as second line therapy, would be a more optimistic choice to make first, than Alimta? I only have one lung left, and I have adenocarcinoma, which was held stable by two cycles of first round chemo, but progressed when we took a two-month break in the chemo.
Your columns and site are so much help, I can’t thank you enough.
Artdobber
I really appreciate your kind words.
Really, the overall numbers are pretty darn comparable for second-line chemo agents like alimta or taxotere and tarceva. They haven’t been directly compared head to head to say whether alimta is better than tarceva or visa versa, but there are trials looking at this, so we’ll get some useful insight in coming months and years. But I didn’t mean to paint a pessimistic view of Alimta. I think it’s among the better drugs in lung cancer, but none of these is as broadly active as we’d hope in previously treated patients.
In the meantime, any of these choices is perfectly appropriate. Even the lung cancer experts have different approaches, but here’s mine. I consider two things particularly important: smoking status and prior response to chemo in first-line treatment.
In a never-smoker who hasn’t gotten tarceva before, I’ll essentially always recommend it for second-line therapy (and would consider it as a first-line treatment). Otherwise, the less a person smoked, and the longer it’s been since they quit, the more likely I’d be to recommend tarceva next. For instance, someone who smoked a half pack per day for 5 years in college and quit 40 years ago would be pretty close to a never-smoker in my book.
For response to prior therapy, someone who had a very good response to chemo that lasted a long time, I’d almost certainly recommend chemo as a next treatment. Conversely, if someone progressed through first-line treatment quickly, I’d recommend the non-chemo option of tarceva. And I’d be kind of in between for someone who had a minor response or stable disease on first-line chemo.
Patient preference also counts for something here, in terms of IV vs. oral drugs, do they like the idea of targeted therapy or feel that chemo is really the treatment of choice for cancer (these are more biases than evidence-based, but if you’ve got choices with similar pros and cons, they’re an appropriate tie-breaker). But in general, I use a continuum from never-smoker to long-term chain-smoker, and another continuum from great prior chemo response to prior progression to help me estimate whether chemo or tarceva is more likely to be beneficial as a second-line therapy for a patient.
-Dr. West
Thanks for the prompt reply. As usual, your opinion/expertise is in close agreement with my oncologist. I smoked so little, I’m considered a never-smoker. I was all set for beginning Tarceva in two days, but today I hear that I’ve got some evidently small (1 cm) met to the brain, so I’m heading for some possible radiation on that first.
Artdobber
I’m sorry about that curveball, Art. I’m glad that’s being treated, and then you can move forward with second-line therapy.
And I’m glad I can help corroborate the input you’re getting from your oncologist, to provide the reassurance of hearing the same thing from two perspectives.
Dear Dr. West. Thank you for your time and efforts on behalf of all of us that are touched by lung cancer. I’m cautiously optimistic about Alimta, but have a quick question regarding mom’s latest CT results. She has just completed two sessions of Alimta and the radiologist reports: “No significant change in left perihilar consolidation, nor in consolidation or mass in the posteromedial left upper lobe measuring roughly 3.7 cm x 2.7 cm on image 16. Small amount of reticulonodular change is present in the anterior left upper lobe, which probably represents inflammation or post obstructive atelectasis. There is a 2 mm peripheral left upper lobe nodule on image 24, which is nonspecific but no definitely seen previously. Small amount of linear scarring is again evident in the left lower lobe. Minimal left pleural effusion is new. No evidence of bulky mediastinal or hilar adenopathy. No bulky axillary or retrocrual adenopathy.
IMPRESSION: Stabe CT scan of the chest with respect to left perihilar consolidation and left posteromedial upper lung consolidation versus mass. Development of minimal left pleural effusion. Small amount of reticulonodular change in the lumbar spine, which is nonspecific but should be followed.
Question:
1. Is the 2mm nodule new cancer.
2. Mild pleural effusion represents progression of disease, doesn’t it. When one presents with pleural effusion, doesn’t that mean the lung cancer is advanced, possibly Stage 4.
Thank you for your continued work on behalf of all of us.
Lisa Smith
something 2 mm is pretty inconclusive, so I would not say it’s definitely a new cancer nodule. It merits close follow-up, but I’d consider something that small to be pretty ambiguous. Same with the effusion. I’d agree that I’d be concerned and somewhat suspicious, but inflammation or several other non-cancer diagnoses can lead to an effusion.
My general approach is that if a scan is so ambiguous, with perhaps a hint of progression, I would not be inclined to stop a well tolerated therapy. If there are ambiguous signals and a hint of progression but the treatment is very rough, I’d be more inclined to change plans. But in general, I want to give the patient the benefit of the doubt. I’ve had situations where I’ve been nearly convinced of recurrence or progression and then found that it wasn’t cancer at all but some benign cause. So I don’t automatically presume the worst.
-Dr. West
Hi Dr. West: One more quick question. Good news for my mom’s latest CT. Alimta has stablized the disease. No evidence of bulky mediastinal involvement or hilar involvement. No evidence of any other disease. She’s been on Alimta for 3 months. Was stable for 1.5 years after initial treatment for stage 3a. Relapsed after 1.5 years. Grew slowly for 6 months before onc treated. Tried Tarceva. Slight progression. Switched to Alimta. Good overall quality of life. Some people say she doesn’t even look sick. Gets tired and wears a Duragesic Patch for severe arm pain (which they have yet to figure out). Anyway, overall not too bad. Am I off base thinking that she will be around for another 2-3 years. I know this is considered third line treatment, but it is still contained in the lung. Thoughts?
Lisa Smith
I just can’t think that far ahead in my own patients — cancer is too unpredictable. It would be really impossible to try to make a prediction in someone who isn’t my patient. Intervals of disease control/non-progression tend to last a shorter time as time goes by and the cancer has been more extensively treated, so in general it’s hard to talk about a prognosis of years in previously treated patients with advanced NSCLC. On the other hand, the natural history of her cancer is clearly indolent, which you know from the 6 month period of non-treatment after recurrence. So no matter what happens with her treatments, it seems that this is likely to have a background of growth on the slow side. I would consider that a factor that would suggest a likelihood of doing better than the general numbers. Overall, we’re not that great at predicting the future, even in our own patients, so I can’t do you or her justice by making a prediction when there is so much I don’t know.
-Dr. West
Dr. West -
My mother was diagnosed with Stage IIIB NSCLC in June 2007. She had a medialstinal mass measuring 3.5cm x 5.5cm. They did 33 treatments of radiation and 4 cycles of Carbo and VP16 although only 2 cycles of chemo were combined with radiation since she had fluid in the lung. After the radiation and chemo they said the mass was dissipated and that she was “clinically in remission.” This only lasted for a couple of months because in November ‘07 they mentioned there was a 1 cm mass right underneath the original mass. In December it was 1.8cm and last week in another cat scan it was measured at 4.0 x 2.5 x 7.5 cm in maximal transverse, AP, and craniocaudal diameters and is partially encasing the anterior wall of the descending thoracic aorta and partially eroding into the left mainstem bronchus. Below is the impression from the last CT-Scan
direct submucosal versus endoluminal invasion of the left mainstem bronchus
partial encasement of the descending thoracic aorta
severe encasement and constriction of the left inferior pulmonary vein.
stable small pericardial effusion
The cardiac chambers are normal in size. No pericardial thickening or nodularity. The thoracic aorta and central pulmonary arteries are normal in caliber and luminal enhancement.
The onc is putting her on Alimta starting next week. She can not receive any more radiation because she has received the maximum amount in her last treatment and this mass is right below the original mass.
Will Alimta help reduce the size of this mass at all or will it just potentially stop it from growing? I’m worried since this mass is severely restricting the pulmonary vein and that she has pericardial effusion that it could cause heart problems if it does not shrink. Should the onc be watching this more closely?
Would you be able to explain some of the CT-Scan impression in Lehman’s terms? The size of the mass scares us but I’m not clear on what these diameters exactly are.
The mass is non-surgical so is there anything else she should be on to help reduce the size of the mass or are we in a situation where Alimta will just help stop the growth and possibly improve her quality of life?
Do you feel they may have miss-diagnosed it as NSCLC and it could be Small Cell? I know small cell is more aggressive and it seems like this tumor is growing awfully fast.
Sorry about the long post but I wanted to make sure you had all the information.
Thanks for all you do!
sajr11
I’m very sorry to hear of your mother’s progression. Unfortunately, there are just too many questions out there, so I don’t have the time to decipher a long and detailed CT report: I need to focus on ones that are more generally helpful. Very individualized questions really need to go to your doctor.
I can say that alimta would have a chance of shrinking the cancer, but only 9% of patients in the large trial of previously treated patients had tumor shrinkage by 50% of its overall estimated volume. Many more had some more minor shrinkage, and in total a little more than half of the patients had stable disease or better.
I really can’t suggest anything further for the oncologist to do if she’s already received the full amount of radiation she can receive safely. If the cancer continues to progress, even following it like a hawk won’t help if there isn’t anything to be done to change the course of the cancer. So using the best systemic (whole body) therapy seems to be a very appropriate plan.
While it’s always possible that there could be confusion between SCLC and NSCLC, I wouldn’t presume that to be the case because of the progression — unfortunately, there’s also plenty of aggressive NSCLC out there too.
-Dr. West
Thanks for your reply. Just 1 more question. What are the dangers of the left inferior pulmonary vein being constricted and the thoracic aorta. Is there any hope or is it to dangerous with all the vital surrounding organs.
sajr
The above posting is regarding my sister, dx with NSCLC. My concern is the significant growth of her tumor and the involvement of the greater vessels. With these findings, would you suggest adding one of the platinum drugs to the Alimta for a greater percentage of shrinkage. We are not looking for a cure, but we need to decrease the size of this mass as much as possible due to her becoming more symptomatic. What are your thoughts? Thank you in advance for your advise.
Robinv
sajr,
I’m not sure exactly what you mean by “is there any hope?”. I don’t think surgery would be featsible. Radiation is a significant possibility when the area hasn’t already received what would be considered the full amount of radiation that is generally safe to normal tissues. Otherwise, the hope is that chemo will keep it at bay, or it just won’t grow much more in that area. Unofrtunately, it is concerning to have a pulmonary vein compromised by obstruction. Nut if people can live with entire lungs removed, it’s also feasible to live without the function of one part of one lung from having it compromised by tumor that leads to lung collapse or a blockage of blood vessels, as may happen here.
Robin,
I would say that adding a platinum drug to alimta would increase the chance of tumor shrinkage pretty modestly, likely in the range of 5-10% higher, for a major response (50% shrinkage). Even for first line, response rates for platinum doublets are generally in the 25-30% range, and you’d expect the second line outcomes to be lower even with the same drugs, just because the cancer has already become resistant to a line of prior chemotherapy. I don’t know if I could judge that it would be advisable vs. added side effects. The doublets, particularly with carboplatin, can be quite well tolerated, but I don’t generally do doublets after first line and think the incremental gain overall is pretty small.
-Dr. West
Thank you for your response to my question re adding platinum drug to Alimta. I think we are all focusing on the extensive involvement of the greater vessels. Our question is since surgical resection is not an option, radiation txmt has been completed, is Alimta our only choice of txmt for my sister. She is only 58 yrs old and we are grasping for any add’l ideas to combat this monster.(cancer) I would think we could use add’l radiation txmt but only for pallitive care of her increased symptoms but I am asking if you have any add’l thoughts about a systemic txmt. Thank you sharing your knowledge with everyone dealing with this horrible disease. Robin
Robinv
Robin,
I only have the recommendations I’ve described throughout these archives for second and third line therapy. I’ve extensively described alimta, taxotere, and tarceva, as well as several investigational agents.
-Dr. West
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