A quick point on the importance of biology over treatment. Years ago, I highlighted the results in the TRIBUTE trial of chemo with placebo or combined with erlotinib (tarceva) at the same time (biomarker study abstract here), which showed that patients with EGFR mutations had a much better survival whether they received an EGFR inhibitor or not:

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   Here, biology was the prevailing factor. We’ve also recently seen that the patients on the IPASS trial of Asian never-smokers or light former smokers who were then randomized to first line chemo or an EGFR inhibitor had a far better survival if their tumor had an EGFR mutation compared to those who did not (see prior post). Similarly, the IPASS trial also showed that patients with EGFR mutations had nearly double the response rate to chemotherapy that patients without EGFR mutations demonstrated. So maybe the benefit of unique biological factors applies to standard chemotherapy as well as “targeted therapies”. Chemotherapy is also targeted and only benefits a subset of patients: we’re just further behind at understanding the relevant targets and discriminating the beneficiaries from others with standard chemo than with agents like EGFR inhibitors.

    The recently published trial of cisplatin/alimta (pemetrexed) vs. cisplatin/gemzar (gemcitabine) (abstract here) showed an interesting result among enrolled never-smokers, who comprised 14-15% of the patients on the 1725 patient trial overall. Although we think of never-smokers as doing especially well with EGFR inhibitors, this trial also showed that never-smokers had a markedly longer median overall survival in both chemotherapy arms compared to current or former smokers (15.9 vs. 10.0 months in the cis/alimta arm; 15.3 vs. 10.3 months for the cis/gem arm).

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   In my last post I outlined the typical clinical scenario for pneumonic bronchioloalveolar carcinoma (BAC), which is typically the mucinous subtype of this unusual disease.  In fact, we are still actively learning a great deal about BAC, enough for the lung cancer experts to begin to develop a more sophisticated view that the mucinous and non-mucinous subtypes have different behaviors and respond differently to treatments.  Here is a case that illustrates a situation that I would consider to be typical for the mucinous, pneumonic form of BAC.

    Ella A. was 74 year-old woman with a very long smoking history of about 50 years, who quit last month in the face of worsening pulmonary and other symptoms.  Specifically, she experienced an initial dry cough that became productive of sputum over a six-month period, during which time she also developed increasing shortness of breath and a 20-pound weight loss for a woman who was pretty slender beforehand.  This led her to her primary care physician, which showed extensive “consolidation”, shadows in both lungs and particularly extensive on the left.  These findings were confirmed on a CT.

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As you might suspect, this led to a referral to a pulmonologist for a brochoscopic biopsy.  The pulmonolgist needed to start her on oxygen before he could do a thorough bronchoscopy.  The biopsy revealed well differentiated BAC, but the pathologist (an expert in lung pathology) didn’t have enough material to specify whether it was mucinous or non-mucinous.

   Frankly, at the time when I first met her, in December of 2006, there were only the early inklings that this could be relevant.  We don’t have much more information since then, except for the anecdotal experiences of myself and a few others who treatment many patients with BAC, which have corroborated the early impression that the well described effectiveness of oral EGFR inhibitors like iressa (gefitinib) and tarceva (erlotinib) in BAC appeared to be limited to the non-mucinous subtype.

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   Let’s return to what happened with Anne S., who I introduced in the last post.  The highlights are that I met this woman in September of 2005, when she was 79, slowing down from many medical issues unrelated to cancer, wary about chemo, and with a cancer that was metastatic but that had progressed only minimally in the months between the initial detection of her cancer and when I first saw her.  We agreed that attentive follow-up made sense.

   And so, I saw her regularly, and her scans showed very minimal progression 6 and 12 weeks after her initial visit with me.  She also felt pretty much the same, bothered primarily by her arthritis, fatigue (which preceded her cancer), and other issues…but no appreciable decline.  In fact, she didn’t really show very convicing progression until late May of 2006, when one liver lesion grew pretty notably, and a new one emerged.  We again discussed the risks and benefits of treatment, and she decided to start single-agent gemcitabine (navelbine is a well-studied option in the elderly, and it’s a fine choice I’ve also given frequently in similar situations, but it does have the inconvenience of generally needing to have a port-a-cath placed, because it can cause a chemical burn if it leaks out from the IV catheter into the surrounding tissues). 

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   Actually, it’s some background information and your blood that’s needed. 

   Memorial Sloan-Kettering is running an important trial that is trying to determine some of the molecular factors that lead some never-smokers to develop lung cancer while other never-smokers don’t.   The trial is just a one-time collection of information in a questionnaire, I believe about medical history and environmental exposures, and submission of two vials of blood.  There is no cost to participants, with all packaging and mail expenses pre-paid, and the registration and additional information is online here. 

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     The European Society for Medical Oncology (ESMO) Congress, similar to ASCO but based in Europe, has been going on in Stockholm, where the results of a study called the First Line Iressa versus Carboplatin/Paclitaxel in Asia Study (taking some liberties to force it into the acronym ”IPASS”) was presented in the Presidential Symposium by my friend and Hong Kong-based colleague Tony Mok.   This study, as shown in the schema below, randomized 1217 Asian patients with advanced NSCLC who had not received prior systemic therapy to either the oral EGFR inhibitor iressa (gefitinib) or the standard chemotherapy carboplatin/taxol (paclitaxel):

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  We’re recognizing more and more that lung cancer in never-smokers (LCINS) is a distinct disease, with different patterns of who gets it, how the cancer behaves, and it responds  to treatments.  But this recognition is still a work in progress, coming from a background in which the party line has been that NSCLC is treated the same regardless of the histologic type (squamous, adenocarcinoma, large cell, or other), smoking history, or other factors.   In fact, it’s fair to say that it’s still appropriate to treat never-smoking patients with the same approach that I described in other posts about NSCLC patients in general.  But I do think of never-smokers a little differently because of its apparently distinct biology, and this does modify my practice recommendations. 

   To me, the guiding point, based on what we know right now, is that never-smokers have a high likelihood of receiving a significant benefit from oral EGFR tyrosine kinase Inhibitors (TKIs) like tarceva and iressa (see prior post).   While the LCINS population isn’t as likely to have a significant response to EGFR TKIs as a population defined  by the presence of an EGFR gene mutation (around 30-50% for never-smokers vs. 60-80% for EGFR mutation-positive patients) , they are a readily identifiable group of patients who consistently have a higher magnitude of benefit with EGFR inhibitors than we’re used to seeing with chemo.   But there are absolutely other factors, since some studies corroborate my own clinical observations treating the LCINS population really demonstrates that Asian never-smoking women are clearly more likely to respond than some other groups, such as Caucasian never-smoking men.

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    In Japan, a different chemotherapy approach than cisplatin doublet chemo has been used in the post-operative setting.  In contrast to the North American and European approach of 3-4 cycles of platinum-based chemo, in Japan they have studied an oral chemotherapy called UFT, a combination of uracil and tegafur.  This combination is in the same family as an old chemo drug called 5-FU that is still used in various settings today, although not commonly in lung cancer.  Nevertheless, this oral chemotherapy, which isn’t and probably won’t become available in the US and several other parts of the world, has been studied in a Japanese population and actually shown to improve survival in patients with stage I NSCLC.  And this year we saw an analysis of the benefit of chemotherapy on the basis of patient age in this trial (abstract here).

The original trial enrolled just under 1000 patients with stage I adenocarcinomas (a remarkably common presentation in Japan, where they really do see a fundamentally different lung cancer biology than we see in North America and Europe, at least).  This focus on patients with adeno NSCLC is based on earlier work that indicated this drug worked preferentially in adenocarcinoma tumors, and randomized patients with stage I tumors to observation or up to two years of daily oral chemotherapy after surgery (abstract here).    As shown in the curves below, there was a modest but significant survival benefit, and nearly all of that benefit was seen in patients with larger, higher risk T2 cancers, rather than the smaller T1 cancers with the lowest risk for recurrence and death:

Interestingly, this is really the most conclusive survival benefit we’ve ever seen for stage I NSCLC, and in the curve for the overall trial population (left curve), the separation of the curves that signifies a survival benefit from treatment doesn’t occur until four years out.   Unfortunately, this is with a drug not available in the US and was a benefit seen only in patients with stage IB adeno NSCLC: we haven’t been able to do another study with UFT to confirm this, but it’s currently a standard treatment in Japan.

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   One of the core ideas in the management of stage III, or locally advanced, NSCLC is that unresectable disease that is being treated with curative intent is most effectively treated with a combination of concurrent systemic (”whole body”) therapy and chest radiation to all of the visible cancer.  The systemic therapy, which has been conventional chemotherapy, is given to both make the radiation work better and to treat potential micrometastatic disease, cancer cells in the bloodstream that can’t be reached by radiation but could potentially be killed off by a treatment that goes throughout the bloodstream.  

   The challenge, though, is that concurrent chemo and radiation is hard on people, with a rate of treatment-related deaths of about 5-7% of people even on clinical trials (which often select for a fitter population than are seen in the “real world” of many ineligible patients).  So we reach a point where the aggressiveness of the treatment can be associated with problems that are as threatening or worse than the underlying disease.  And this is a particular problem for older and/or frailer patients, which happens to cover a significant proportion of people with lung cancer.

   Part of the promise of targeted therapies all along has been that they could potentially substitute for standard chemotherapy as a systemic therapy that is perhaps as effective as chemo but with fewer side effects.  Most of our work with these agents has been to just add them to our current standards, but it still makes sense to consider using them as a substitute in patients for whom conventional chemo is really at the upper limits of what is tolerable.  And it’s clear that doing chemo concurrent with radiation is overall more effective than doing them sequentially, but perhaps we could get the tolerability of a sequential approach with the efficacy of concurrent therapy by doing a program of targeted therapy (and no chemo) concurrent with chest radiation.

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One of my earliest posts when I started OncTalk was on the use of oral inhibitors of the epidermal growth factor receptor (EGFR), one of the growth signals that is often over-active in cancer cells, against advanced bronchioloalveolar carcinoma (BAC), a unique subtype of lung cancer that tends to grow within the lungs, sometimes slowly, and not progress elsewhere. These EGFR inhbitors like iressa (gefitinib) and tarceva (erlotinib) have certainly been well studied in NSCLC in general, but both of these drugs have been a focus of particular attention as a treatment for BAC. In fact, the largest trial that has yet been conducted in advanced BAC is one that I led, called SWOG 0126, that gave iressa at 500 mg by mouth daily (actually twice the dose that was eventually settled on, but possibly a more effective dose) to 135 eligible patients with advanced BAC. My colleagues and I published the results of this trial a couple of years ago (abstract here), but this year at ASCO I presented the results with longer-term follow up (abstract here), which yielded some interesting findings.

Obviously, the response rates and side effects didn’t change with a couple of years of longer-term follow up. Nor did the median progression-free and overall survival numbers, since those reflect the point at which half of the patients will have demonstrated progression or have died:

It’s worth noting that while this study enrolled both patients who had never been previously treated and some other patients who had received prior chemotherapy, both the chemo-naive and previously treated patients had the same progression-free and overall survival results, as shown in the superimposed curves shown above.

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   One of the initial appeals of targeted therapies like tarceva (erlotinib) was that they may have fewer side effects and emerge as an alternative to standard chemo for some people.   And one of the most appealing areas for offering a good alternative to standard chemo has been in the setting of older patients, who may be more wary of side effects and/or have additional medical problems than younger patients.  

   A theme that has emerged very consistently in studies of elderly patients in lung cancer, and largely in oncology in general, is that fit older patients without many medical problems are very likely to do every bit as well as younger patients.  Although studies of older patients with lung cancer have largely paired the elderly and “poor risk”/frailer patients (performance status of 2, corresponding to being symptomatic, a little limited in activities, but spending more than half of the day in bed or a chair) in pooled trials.  More recently, though, we’ve come to recognize that these are overlapping but definititely distinct groups.   We also learned in a prior post that unselected patients (not singled out by things like having never smoked, or having an EGFR mutation, for instance), with a marginal performance status who receive tarceva instead of standard chemo clearly do less well than patients who get standard chemo.  But how well do older patients do with tarceva, independent of performance status?  This is an important question now that more than half of all newly diagnosed lung cancer patients are over 70.  A couple of trials help shape our thinking here.

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