I’ve covered stage IIIA NSCLC in several prior posts, mentioning that it’s a clinical setting that is among the most controversial, but I don’t think I’ve really described my real world approach. To review, the controversy is that for stage IIIA NSCLC with mediastinal lymph node involvement on the same side as the tumor (N2 nodes), some people would recommend surgery as a main treatment strategy, and others would recommend chemo and radiation without surgery. The trials that have directly compared a surgical to a non-surgical approach have shown no significant survival benefit for either approach. However, one key study demonstrated that patients who underwent surgery had a lower risk of a recurrence of lung cancer, but this was largely offset by a higher risk of treatment complications and even death related to the more aggressive treatment of chemo and radiation followed by surgery (see prior post).
There is also the question for people who are planned to undergo surgery of whether they should start with surgery or receive “induction”/neo-adjuvant therapy beforehand. And if they receive induction therapy, should it be with chemo alone or chemo and radiation together? The typical standard is that for patients who have mediastinal node involvement identified before planned surgery, we usually give chemo with or without radiation as well before surgery. You could make the argument that it’s just as good to give it afterward, but stage III NSCLC is a setting in which the risk of recurrence with surgery alone is very high, and I’d feel far more optimistic about getting in chemo +/- radiation as well as surgery by starting with induction therapy and following with surgery, rather than starting with surgery and hoping to get additional therapy post-operatively. Too many patients can’t or won’t take more treatment after a big lung surgery to really expect that you can deliver it in the adjuvant (post-operative) setting.
Most of what I write about here highlights the evidence supporting treatments, and that’s certainly how we strive to practice oncology. But the reality is that patients and doctors often find themselves in the middle of settings where we don’t have any answers and need to rely on judgment, or we think we can potentially do better by defying conventional wisdom. Doctors lie all along the spectrum of being “data-driven” on one end and being a “cowboy” on the other end. The general perception is that many academics are more evidence-based, but I’m not sure that’s true: experts defy the guidelines all the time and say that the key is knowing when to follow and when to deviate from them.
One of the typical places in which we find ourselves at odds with a lack of evidence is in treating patients beyond about third line treatment. We have trials that show the evidence of a limited number of our treatments for NSCLC out to third line, and second line for SCLC. Most patients run out of energy and/or interest in treatment by about that time, but some patients have slow-growing and/or particularly responsive cancers and come back after multiple lines of treatment feeling well enough to come back to the clinic and ask, “what next?” Many people participating here are beyond the point where we have evidence that further treatment is beneficial. How do we manage these situations?
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.
The setting of unresectable, stage IIIA or IIIB NSCLC (without a malignant pleural effusion) is currently one for which what we feel is best for the patient isn’t necessarily something for which we have good evidence. For fit patients, there is a strong consensus that giving concurrent chemo with radiation provides a modestly but consistently higher cure rate than giving chemo and radiation sequentially. But that concurrent chemoradiation plan lasts for only 6-8 weeks, but whether there’s more we should be doing, or what we should do, is entirely unclear.
As described in a prior post, several studies in the last decade have shown that about two cycles or 6-8 weeks of weekly chemotherapy along with about 60-66 Gray of radiation over 6-8 weeks is associated with the best survival results we’ve seen in unresectable, locally advanced NSCLC (somewhere in the 20% range long-term, and a median of about 16-18 months). There are two main approaches in North America for the chemotherapy. Some use the SWOG approach that showed very promising early results (prior post here), giving cisplatin and etoposide. The other very common alternative that is widely used in a community setting is weekly carboplatin/taxol. Until very recently had relatively little published experience to support it, but in the last few years now has been included in a few trials that demonstrate survival in the same ballpark as what we routinely see with cisplatin-based chemo: examples include RTOG trials such as described in a prior post and another abstract.
I go to many meetings in which cases are presented and medical oncologists provide their repsonses about how they’d be inclined to treat a patient. Although we bemoan the lack of much progress in managing small cell lung cancer, one of the effects of that is that there is pretty strong uniformity in how we manage it, since the standards are quite well established.
Although several years ago there was a small Japanese trial that showed a significant survival benefit for the combination of cisplatin/irinotecan compared with cisplatin/etoposide, which led to growing use of irinotecan instead of etoposide outside of the US as well, North American trials over the last few years have not shown a similar benefit (summarized in prior post here). This difference in outcomes by geography is likely real and related to relevant genetic differences in how Japanese and Caucasian patients process and respond to irinotecan vs. etoposide. The North American studies have shown that the different regimens are comparable in activity, but that irintecan is associated with significant diarrhea, while etoposide is associated with more significant drops in blood counts.
These days, the vast majority of US-based oncologists give a platinum with etoposide, fairly split between cisplatin and carboplatin. My preference has generally been to use carboplatin in a setting in which we can’t cure the cancer, and for which there is a little evidence that they produce comparable results (see prior post). In fact, historically most of the studies of ED-SCLC have used cisplatin/etoposide as the standard treatment, but one recent trial used carboplatin/etoposide and produced results every bit as good as what we see with cisplatin (see prior post). This corroborated the more limited avidence that carboplatin was a less challenging but very comparable alternative to cisplatin.
To begin with, my overall impression is that the preponderance of evidence on adjuvant (post-operative) chemotherapy supports that it can reduce the recurrence risk and improve the survival at five years, which I’d presume to be pretty close to the “cure rate”. The benefit isn’t uniformly distributed for all patients: higher risk patients, as defined by stage and other additional factors like number of lymph nodes involved and the grade of the cancer, also matter. Our current standards converge on recommendations favoring post-operative chemo for stage II patients and the minority of patients who have “surprise” N2 nodal disease not detected before surgery and are therefore stage IIIA and without evidence of residual disease. These patients derive a clinically significant benefit from chemo that more than offsets the small but real risk of serious side effects.
I consider it important to remember that 0.5 – 1% of patients on most of the clinical trials of adjuvant chemotherapy died from the treatment, and the trial population is non-representative of the broader “real world” population that is sicker and older than the patients who went on these trials, on average. And the most recent updates of one large adjuvant trial (prior post here) raises the specter that the risk from chemo may be not be captured completely in the first five years and that the outcomes may be more disappointing with follow-up beyond five years. Overall, I consider this to be far more of a concern for the patients I would already consider to be marginal for adjuvant chemo — stage IB, or those who are already pretty frail and may be more harmed than helped by chemo. The emerging story is telling me that it’s not just that adjuvant chemo either helps or it doesn’t help. While it may help some, there could be detrimental effects, so it’s worth being judicious in deciding whether to pursue it: more is not necessarily better.