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The Work We Still Need to Do
I just gave a continuing medical education talk to a group of general physicians at an out of town community hospital, and in that process I stepped out of my bubble. Spending most of my life working with cancer patients, oncologists, and other physicians at my own tertiary hospital, I primarily encounter people who share a commitment to dedicating resources and a great deal of research effort to cancer patients in general, including lung cancer. While we know that there is a terrible lack of awareness that lung cancer is the leading cause of cancer death in the US (about 28% for both men and women) and that it’s woefully underfunded, we’re all preaching to the choir here. In my talk today, though, to physicians who don’t have a particular focus on or interest in cancer, I was saddened and disappointed that I was interrupted so that someone could ask why we’re even treating people who continue to smoke and whether our treatments are beneficial enough to treat people with metastatic lung cancer at all.
To some, having the limitation of not offering curative therapy, especially if we’re considering expensive treatment, makes it tempting to be derisive that treatment is of value. We see far more patients with improvements in survival measured in years, but even if it’s months, the vast majority of my patients consider a survival benefit of “good time” with minimal side effects to be exceptionally valuable. The irony is that its often physicians who will be tenacious about pursuing every treatment that is remotely useful, and then many others beyond that, without a remote concern about the costs for the health care system, if it’s their family member affected. But in the abstract, people who I expect would be more sensitive and insightful can be painfully nihilistic.
There have been a few recent trials that have demonstrated that a surprisingly high proportion of people diagnosed with lung cancer are never referred to another physician for treatment. As oncologists, it’s hard for us to imagine why we wouldn’t be offered the opportunity to at least discuss the potential value of treatment. But today I saw a glimpse of the mindset of “why bother?”.
Basics of Bronchioloalveolar Carcinoma (BAC)
Bronchioloalveolar carcinoma, or BAC, is a unique subtype of non-small cell lung cancer (NSCLC) that has unique features in terms of the demographics of who gets it, how it appears on scans, how it often behaves, and potentially in how it responds to treatment. It is a subset of lung cancer for which most of what we know emerged in the last 10 years, with our understanding of this entity, and even the definition of BAC, still evolving.
What is BAC?
BAC was first identified and defined as a separate subtype of lung cancer by Dr. Averill Liebow in 1960. At that time, he highlighted it as a form of well differentiated adenocarcinoma of the lung that appeared to not be able to invade the surrounding lung scaffolding and spread within the lung(s), presumably aerogenously and/or through lymphatic channels.
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NATCH: Good Question, Bad Trial
As I mentioned in my last post on the recent results on pre-operative (neoadjuvant) chemotherapy, the results of this work failed to achieve statistical significance but did appear to be associated with a degree of benefit comparable to the magnitude of benefit seen with post-operative (adjuvant) chemotherapy, but the neoadjuvant trials were smaller and therefore underpowered. At the same time, there are differences in the patients who receive neoadjuvant vs. adjuvant chemotherapy. Specifically, the patient population getting pre-operative treatment are a broader population that hasn’t had the patients with the most aggressive disease or marginal performance status drop out before getting to the post-operative therapy part. The patients enrolling on adjuvant therapy trials had to have gone through surgery, tolerated it OK, been found to not have more advanced disease, and still feel up to pursuing more treatment: they’ve already cleared several hurdles.
The best way to directly compare a pre-operative to a post-operative chemotherapy strategy is to directly compare the same patients randomized in the same trial. This was the premise of the Neoadjuvant vs. Adjuvant Taxol/Carbo Hope (NATCH) trial, which randomized 624 patients to either surgery alone, carbo/taxol for three cycles pre-operatively, or the same chemo post-operatively. Enrolled patients could have anywhere from stage IA (with at least a 2 cm tumor) to stage IIIA N2 NSCLC.
ASCO Update on Pre-Operative Chemotherapy
Post-operative, also known as adjuvant chemotherapy, is the established method for delivering systemic therapy to improve long-term outcomes beyond what surgery alone can deliver. An alternative approach, though, is to give treatment prior to surgery. This gives the potential advantage of treating potential micrometastatic disease at the earliest opportunity, identifying the response to treatment given rather than treating “blind” with no disease to follow, and potentially delivering treatment more reliably because more patients will receive treatment as planned than in the post-operative setting, where many patients may drop out of consideration for chemo as they contend with recovering from surgery and potentially having complications.
Still, the higher profile pre-operative chemotherapy studies haven’t been positive, or at least not positive enough. But it’s worth reviewing what’s being considered a negative study.
First, there was the SWOG 9900 trial, designed with a plan to enroll 600 patients to detect the differences they hoped to, but closing after only 354 were enrolled, in the face of a series of positive post-operative trials making it very difficult to continue to enroll patients on a trial of pre-op chemo vs. up front surgery, with no plan for adjuvant chemotherapy. This trial, for patients with stage IB – IIIA NSCLC (without N2 nodal disease, a higher risk group), gave 3 cycles of pre-operative carboplatin/Taxol (paclitaxel) and was reported as showing a non-significant trend toward more favorable survival in the chemotherapy recipients. Results are illustrated on the curves for progression-free and overall survival shown below:
(click on images to enlarge)
Though these differences were not quite statistically significant, they both reflected an approximately 20% improvement with chemotherapy compared with surgery alone. Though some have speculated that these results may have been more favorable if a cisplatin-based regimen were used, the magnitude of relative improvement here with carbo/taxol seems very comparable to the results we’ve seen in positive adjuvant trials with cisplatin-based regimens, but the trial was definitely underpowered, closing with just under 60% of their intended patient enrollment completed.
Changing Clinical Practice: The Evidence that Convinced Me Many People with Advanced NSCLC Should Have Up Front Molecular Testing
The question of which patients to test for an EGFR mutation, and when, has become one of the most timely and rapidly changing ones in lung cancer. The IPASS trial was a landmark study that definitively illustrated that molecular testing overshadows clinical selection for EGFR tyrosine kinase inhibitor (TKI)-based therapy, demonstrating that the 60% of Asian never-smoker or light former smoking patients with advanced lung adenocarcinoma on this trial that had an activating EGFR mutation demonstrated a significantly higher response rate and progression-free survival (PFS) with the EGFR tyrosine kinase inhibitor (TKI) Iressa (gefitinib) than with standard chemotherapy (carboplatin/Taxol (paclitaxel) in this particular study). In contrast, the 40% of patients with the same clinical characteristics on this trial but without an EGFR mutation had a significantly better response rate and PFS with standard chemotherapy. Overall survival (OS) results were preliminary and revealed the same mutation-dependent trends, though they were not significantly different in the approximately one third of patients who had tumor tissue available for mutation testing.
My take on this work was that there was now compelling evidence that clinical selection of patients to receive chemotherapy vs. EGFR-based first line therapy is most definitely inferior to molecular selection, but this was just one study and a retrospective analysis of mutation status in only a limited subset of patients, and perhaps the trend of an OS difference could be reduced if we work to ensure that patients all get access to the same agents over time.
Essentially, the question to me was that even if some patients are better served by receiving one treatment vs. another, and this can largely be predicted by the presence or absence of an EGFR mutation, does it really matter whether the optimal treatment for that particular patient is given first line or second line? Does order of treatment matter if everyone gets the opportunity to receive the same treatments over time? A few very recently presented studies corroborate the findings from IPASS in a population identified by prospective EGFR mutation testing and lead me to be newly convinced that, at least for patients with an adenocarcinoma or those with little or no smoking history, order of treatment can make a meaningful difference, so it’s ideal to do molecular testing before starting systemic therapy.
New Data on Continuation Maintenance Therapy for Advanced NSCLC
A lot of new data have emerged over the last 2-3 years that have addressed the concept of “maintenance therapy” for patients with advanced NSCLC (see Dr. Socinski’s excellent podcast for a general review). The basic idea is that a patient is treated with first line chemo-based treatment, with or without the angiogenesis in inhibitor Avastin (bevacizumab), and the fortunate majority have some degree of tumor shrinkage or at least stable disease. The degree of benefit from each subsequent cycle of chemotherapy tends to decrease with further treatments, so you reach a point of diminishing returns for an often-challenging two or three-drug combination. While the well-established standard up until a few years ago had been to stop first line therapy and observe a patient for progression before initiating second line treatment, several trials in the last few years have demonstrated that lighter ongoing maintenance therapy, more to suppress the cancer at its current state of prior response and non-progression than to markedly shrink the cancer further, provides a very significant improvement in progression-free survival, and a less clear but at least strongly suggested overall survival benefit (the trials showing a significant improvement in overall survival have some substantial flaws).
There are two basic concepts of maintenance therapy: one is switch maintenance therapy, in which someone stops all of the first line drugs and switches to a new therapy to maintain the response. It has the theoretical advantage of treating the cancer from a new angle, with an agent that the remaining cancer has not had the opportunity to develop resistance to. The approvals of both Alimta (pemetrexed) and Tarceva (erlotinib) as maintenance therapies are based on this concept. In contrast, continuation maintenance therapy is when one or more of the agents from the first line setting is continued after a fixed number of cycles of first line therapy. We haven’t had much data on this concept with modern chemo approaches, but this year at ASCO, a couple of interesting trials were presented that provided some additional insight on this approach (though oncologists often use this approach with Avastin and Alimta, we haven’t seen data that demonstrate continuation maintenance with these agents is beneficial).
Update on ATLAS: Overall survival
We learned several months ago that the ATLAS trial of maintenance Avastin (bevacizumab) with either Tarceva (erlotinib) or placebo did not demonstrate a significant improvement in overall survival (OS) with Tarceva, despite the fact that it was associated with an improvement in progression-free survival (PFS). This is in contrast with the similar trial called SATURN that randomized advanced NSCLC patients after first line chemo to maintenance Tarceva vs. placebo, but without the Avastin during and after first line chemo, as SATURN demonstrated a significant improvement in OS along with a significant improvement in PFS.
In Dr. Mark Socinski’s great overview of the topic of maintenance therapy, he noted these discrepant results, with no obvious explanation. We received additional information about the OS results at ASCO, where it was reported that at the latest time point of analysis, in July of 2009, the median OS was 15.9 months vs. 13.9 months, favoring the addition of Tarceva. This corresponded with a hazard ratio of 0.90, or 10% improvement, over the entire course of treatment, a result that was not statistically significant. The overall survival curves are shown below:
(click on image to enlarge)
Admittedly, it doesn’t look like a major separation, but there is a modest advantage with the combination. You can decide whether that’s a glass half empty or half full.
Case Discussion on Adjuvant Therapy for Stage IB NSCLC with Dr. Nasser Hanna
It’s been a few months since I sat down with my friend, Dr. Nasser Hanna, a great lung cancer expert from Indiana University, and also a friend in the field. Those of you who have been following GRACE content for a while may have come across his name: he’s led a few of the more important trials that are part of our current core knowledge in lung cancer now, such as the trial that directly compared Alimta (pemetrexed) to Taxotere (docetaxel) as second line therapy for advanced NSCLC; the Hoosier Oncology Group (HOG) trial that showed no benefit to consolidation Taxotere after chemo/radiation for stage III NSCLC; a trial of maintenance therapy with oral etoposide after initial cisplatin/etoposide for extensive stage small cell lung cancer, as well as others.
Here’s a transcript and a few key images from our discussion of a challenging case of an elderly woman considering the merits of post-operative chemotherapy for stage IB NSCLC. (I’ll just note that this format of presenting a transcript and a few figures is a fast, cheaper way for us to present the content of conversations we’ve been turning into podcasts until this point. It may be easier to just have it here online, and cuts our costs. If you have a definite preference for the audio/visual format of a podcast vs. this, please voice that opinion).
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Dr. West: Hi, I’m Jack West, Medical Oncologist and President of GRACE, The Global Resource for Advancing Cancer Education. I’m here today with Dr. Nasser Hanna who is Associate Professor in the Department of Medicine, a Medical Oncologist at Indiana University and he was good enough to sit with me and talk about a few complex cases, so thanks for taking the time.
Dr. Hanna: Thanks for having me.
Dr. West: Let’s start with a challenging type of situation that isn’t rare in the adjuvant setting. I saw a 73 year old woman…use to smoke up to a couple of packs per day for fifty years and brought her self down to a few cigarettes per day. She has a good performance status and several months ago developed a worse cough, productive of some clear sputum, no hemoptysis and she was prescribed antibiotics but didn’t get better.
Positive trial for Abraxane in NSCLC: Follow-up From ASCO
Three months ago, I discussed the press release from Abraxis reporting that the phase III trial of carbo/Abraxane (nanoparticle albumin-bound paclitaxel) vs. carbo/taxol (paclitaxel) showed a significant benefit for higher response rate in the Abraxane arm. Carboplatin was given one day every three weeks, as was taxol, and Abraxane was given every week (no break). We received more information, though not a lot more, with the presentation at ASCO earlier this month.
The trial enrolled 1053 patients with previously untreated advanced NSCLC, the majority from Russia and the Ukraine, to either standard carbo/taxol or the albumen-bound form that doesn’t require steroid pretreatment and has a somewhat different toxicity profile. We don’t have progression-free survival (PFS) or overall survival (OS) data yet, but we did get some numbers for response rates. Specifically, according to a pre-planned independent radiologist review, the carbo/Abraxane arm had a RR of 33%, compared with 25% for carbo/taxol. The numbers were a little higher in the investigator-reported numbers, but with essentially the same difference (37% vs. 30%).
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Is Combining Chemo and an Oral EGFR Inhibitor Helpful, Harmful, or Neither?
A central question since the introduction of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like Tarceva (erlotinib) and Iressa (gefitinib) has been how best to use them. Specifically, one standard way that we integrate new agents in cancer care is to combine them with the treatment that is our current standard of care. However, four large trials of first line doublet chemo with or without Iressa (the INTACT-1 and INTACT-2 trials) or Tarceva (TALENT and TRIBUTE trials) were both definitively negative. One exception was that the subgroup of never-smokers who received carboplatin/taxol (paclitaxel) with concurrent Tarceva on the TRIBUTE trial actually did significantly better than never-smokers who received chemo alone.
(click on image to enlarge)
However, one important issue with the curves above is that the group receiving Tarceva doesn’t really seem to do better (as indicated by the separation of the curves) until about 6 months into the trial.
And because the chemotherapy portion was limited to six cycles given every three weeks, this means that the recipients of Tarceva didn’t really seem to do better until they had completed chemotherapy and were continuing on Tarceva alone. This, along with some other suggestive bits of inconclusive evidence, led me to be quite disinclined to give an EGFR concurrent with standard chemotherapy, out of concern that they may even be antagonistic with each other. I think a very relevant test would be chemo/Tarceva vs. Tarceva alone in never-smokers, or better yet, people with an EGFR mutation, but the TRIBUTE trial didn’t test was chemo/Tarceva vs. Tarceva alone.
But a trial by the Cancer and Leukemia Group B (CALGB) (Cancer and Leukemia Group A is long gone), known as CALGB 30406, has tried to address this question directly.
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