Though there are many presentations to discuss in the wake of ASCO, we’ll need to pace ourselves on these.  I and some of the other faculty members will offer thoughts on some of these in the coming weeks, and we also have our upcoming post-ASCO review on June 23rd (click here to learn more and sign up for this free online program).

Today we saw the results of a couple of long-awaited trials of treatment approaches that represented a couple of the more promising concepts for moving forward in our treatment of extensive SCLC, and I’ll cover the first of these today (though only with the benefit of my notes, rather than as many details as I’d like, so these comments are subject to revision and added details later).  Amrubicin has been the subject of some prior  discussion here, but that discussion focused on smaller, phase II trials; we’ve needed the results of a randomized phase III trial that directly compares the chemo agent amrubicin as a single agent to our current standard for Hycamtin (topotecan).  The ACT-1 trial in enrolled 637 patients with extensive disease SCLC who had all received first line therapy and then relapsed — the trial included patients who had a “sensitive” relapse, 3 or more months after prior chemo had ended, as well as “resistant” relapse, which is marked by progression within 3 months of prior chemo ending (pretty evenly split at nearly 50/50 on the trial).  Patients were randomized 2:1 to either amrubicin at 40 mg/m2 IV on days 1-3 of a 21 day cycle, or topotecan at 1.5 mg/m2 IV days 1-5 of a 21 day cycle.

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   Here is the discussion about the study of picoplatin vs. placebo for relapsed SCLC, from the post-ASCO review that I did with Dr. Pennell.  Unfortunately, this work was an overall disappointment, not quite beating placebo in a setting for which we already have a more active alternative.  Here’s the transcript and figures from that portion of the discussion.

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Dr. West: So we’ll turn to the SPEAR trial.  This is a small-cell study with picoplatin which has been one that has been on the radar for small cell for several years at this point.  And this is a randomized trial, a 2 to 1 randomization, of patients who had previously received chemotherapy for extensive small-cell lung cancer, and this was for patients who had relapsed within six month,s with the thought being that the patients who actually progressed beyond six months would often get their prior chemo instead.

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   So patients were randomized to picoplatin with supportive care or one third of patients getting supportive care alone, and the trial looked primarily at overall survival. 

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This is the second of two parts in the Reference Library by Dr. Gadgeel on small cell lung cancer.

Patients with Limited Stage Small Cell Lung Cancer

As stated in the prior chapter from the reference library on basic principles and workup of small cell lung cancer (SCLC), in patients with limited disease (LD)-SCLC, the cancer is only detected in the lung, or the lung and the lymph nodes. But even if it is only detected in these sites it is known, based on prior studies, we remain concerned that the cancer has spread to other parts of the body but that it has not yet grown in these other sites for it to be seen on the scans.

It is for this reason chemotherapy is always included in the treatment of LD-SCLC . Chemotherapy goes throughout the body and therefore will not only attack the cancer visible in the primary lung tumor and the lymph nodes, but also the SCLC cells in the other parts of the body that may exist but remain invisible on the scans.

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Here is the last case I discussed several months ago with Dr. Nasser Hanna, lung cancer expert at Indiana University.  After two cases that included never or light former smokers, which he joked that I saw far more of than he did, we changed direction to cover current issues in managing extensive stage small cell lung  cancer, a field in which he’s been a leader.

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Dr. West: Let’s turn to a final case: a 57-year-old currently smoking woman, with a 50 pack year smoking history, who first developed malaise and a cough about 6 months prior to her presentation.  She felt her symptoms may have spontaneously improved transiently, but 6 weeks prior to her presentation, she developed non-exertional left chest pain and slight hemoptysis.  She was not short of breath, had no weight loss, and she presented to her primary care physician and was found to have an abnormal chest x-ray followed by a CT.

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A few weeks ago, I received an email from a colleague at an affiliated hospital with the title, “Another one bites the dust.” Now I love Queen as much as the next guy, but I don’t like seeing this line in reference to new oncology drugs. In this case, the drug was picoplatin.

Picoplatin is a novel platinum drug, somewhat like cisplatin or carboplatin. Like most chemotherapy, it works by poisoning DNA, causing rapidly dividing cells to die. As you can see, it shares the common platinum core with our old “friend” cisplatin, but the shape has been modified. The idea was that the drug might work in tumors that were resistant to cisplatin.

Picoplatin

Cisplatin

Picoplatin looked good in early studies, even earning attention on GRACE. Last year, Dr. West outlined the vital stats for the phase II of 77 patients for this new compound in 2nd line SCLC:

• Good side effect profile
• 10% response rate
• Median progression-free survival of 10 weeks
• Median survival of 27 weeks

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   The development of targeted therapy drugs has improved survival for patients with NSCLC, and the “pipeline” of agents in development awaiting further testing in clinical trials seems to be increasing by the day.  The improvements in survival in particular subpopulations of patients with NSCLC inspires both patients and physicians who treat lung cancer to hope that similar gains may be made, perhaps incrementally, for patients in all subpopulations of NSCLC.

    In contrast, progress in small cell lung cancer (SCLC) has been disappointingly slow.  Although there was hope initially about improved survival with the combination of cisplatin and irinotecan over the “old standard” of cisplatin with etoposide based upon a trial in Japan, two randomized trials in a more heterogeneous North American population, one trial community-based and another conducted by SWOG, failed to show any survival advantage.  The greatest gains we have thus seen recently for patients with SCLC come from radiation, with twice daily radiation improving survival for patients with limited-stage disease (for those patients who may be able to tolerate the increased toxicities) and prophylactic cranial irradiation (PCI) improving survival for patients with extensive stage disease.

   This frustrating lack of improvement from a chemotherapy front does not come from lack of effort. Much like for NSCLC, a large number of targeted therapy drugs have been tested in SCLC, but with no major breakthroughs.

   But lung cancer doctors are by definition optimists, and we are always hopeful that breakthroughs that make real differences in the lives of our patients may be just around the corner. One of the active areas of research involves BCL-2 inhibitors. BCL-2 is a protein involved in cell survival, and is overexpressed in many cancers, including SCLC. Overexpression of BCL-2 helps to protect a cancer cell from dying, and increased levels of BCL-2 expression help make a cancer cell more resistant to chemotherapy.

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  I recently had the opportunity to sit down with Dr. Toni Wozniak, Moedical Oncologist and lung cancer expert at the Barbara A. Karmanos Cancer Center at Wayne State University in Detroit, MI.  We covered several topics, including SCLC, the subject of this podcast. It is an audio interview but includes a few figures that are synchronized with the audio on the video version, or you can download the pdf of the figures and just follow along with the audio.

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    As with some prior podcasts, it’s primarily audio, but with some synchronized figures that pop up on the video version, or you can download a pdf file with the images to go with the audio.  There’s also a transcript available to download.

Wozniak SCLC figures

Wozniak SCLC Transcript

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Podcast: Play in new window | Download

    Several years ago, I participated in a clinical trial with a combination of carboplatin and irinotecan for treatment of extensive SCLC, just now being published (abstract here).   As a bit of background about the potential utility of irinotecan, the well established cornerstone of treatment of extensive SCLC for about two decades has been a platinum agent (cisplatin or carboplatin) with etoposide, but an important trial in Japan suggested that a cisplatin/irinotecan regimen may be superior to cisplatin/etoposide (abstract here).  Subsequent work done in the US did not support that conclusion, and one leading consideration is that there are meaningful differences in the activity and side effect profiles of different chemotherapy drugs in different racial populations, due to factors like the enzymes that alter metabolism of these agents.  Nevertheless, irinotecan and its cousin topotecan are still high on the list of drugs most active in SCLC.

    The clinical trial in which I participated combined irinotecan with carboplatin, the alternative to cisplatin that is often substituted because of generally comparable activity and a more favorable side effect profile.  In this trial, both agents were given IV on a single day every three weeks.  There were two different groups of patients enrolled, with 40 patients in each: one had received no prior treatment for extensive SCLC, and the other had previously received first line chemotherapy (with cisplatin or carboplatin and etoposide) and had now relapsed.  For the group that had received prior chemo, a lower dose of irinotecan was given (150 mg/square meter vs. 200 mg/square meter every three weeks).  Patients received up to six cycles of this combination.

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   The treatment of relapsed SCLC isn’t especially controversial, because this is an area where there aren’t enough breakthroughs.  In someone fit enough to perform their own activities of daily living and getting out of the house, the main question is how long it has been since they completed their first line treatment.  Although some oncologists use a threshold of 6 months and others 12 months, most oncologists are inclined to recommend returning to the initial chemo regimen (most commonly cisplatin or carboplatin with etoposide), and I do the same, with a 6 month progression-free interval as my trigger.  That’s definitely a minority of patients, and for the rest I usually recommend topotecan, if we decide to pursue additional chemotherapy.  Irinotecan is another reasonable option, although without a proven second line benefit, but it certainly has activity in SCLC.   One of the limitations of topotecan until recently has been that it’s been available only as an IV formulation, and the standard and well studied way of giving it has been for 5 days in a row every three weeks.  That’s a real pain, frankly, and the new and recently FDA-approved oral tablets that have also been shown to have the same activity will make it a far more convenient therapy for everyone.    

    Additional alternatives, either instead of or after topotecan, include the aforementioned irinotecan, as well as gemcitabine, the taxanes, as well as navelbine (although not alimta, as this agent has been shown to be very dependent on histology and quite underwhelming against SCLC, as described in a prior post).   Among options that I might particularly consider as off the beaten path but particularly intriguing for unusually fit patients with relapsed SCLC is a combination of carboplatin/irinotecan given every three weeks, based on a clinical trial in which I participated (abstract here, manuscript submitted for publication.  But this wouldn’t be considered a standard approach.

   There’s also little question that clinical trials are especially appealing for relapsed SCLC, where we all hope to do better and develop newer treatments.  Amrubucin has certainly generated a good deal of deserved enthusiasm (as described in a prior post), as well as some hope for picoplatin (see prior post).  

   That said, many of my patients with relapsed SCLC have had a marginal/poor performance status, or a disinclination to pursue aggressive anticancer therapy  for relapsed SCLC when the benefits are more subtle than we’d want them to be.  A significant proportion have elected to focus on maximizing their comfort and foregoing more treatment, a reasonable decision that I’ve also been happy to support.

   In my earliest introductory post about SCLC, I described the typical staging breakdown used clinically, which is essentially divided into limited disease SCLC (LD-SCLC), which is typically treated with chemo and chest radiation together, with curative intent, and extensive disease SCLC (ED-SCLC), which is typically treated with chemo alone and is not considered conventionally curable.  But one of the murky areas in SCLC staging is the situation of what is limited disease except for a pleural effusion on the same side as the main tumor (called an “ipsilateral” pleural effusion) .   In some trials and at some centers, this situation is considered ED-SCLC, while at others, it’s considered LD-SCLC.  On the diagram below, an ipsilateral pleural effusion is designated as a controversial staging question:

   A recently published report from Japan (abstract here) describes the experience of 63 patients with LD-SCLC and an ipsilateral pleural effusion.  This retrospective review of patients over several years who were all treated at the same center compared the outcomes of patients who initially received chemotherapy and then received chest radiation if their effusion had resolved to the experience of patients who didn’t receive radiation after their effusion resolved.  They also compared the results for these groups to outcomes in the patients whose effusions didn’t resolve after chemo.

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