While progress in small cell lung cancer (SCLC) has been slow, over the past few years there have been leads in management of extensive disease that have introduced a potential change in the standard of care based on better results. Extensive disease SCLC, or ED-SCLC, is defined by having cancer that has spread outside of the region that can safely be covered by a radiation port (more details and relevant figure in SCLC 101 post), and this accounts for approximately two thirds of SCLC cases. Patients can often show very rapid cancer progression and clinical deterioration, but fortunately initial treatment very often leads to rapid and dramatic improvement, although we are not able to cure ED-SCLC.

Now, a history lesson. First, oncologists established that chemo combinations did better than just starting with single drugs. What emerged as the old standard chemo regimen was a combination called CAV (cyclophosphamide, adriamycin, and vincristine -- can you see why we use acronyms?). Then, about 15 years ago, the relatively new combination of cisplatin and etoposide (now far from new) was shown to either do as well or better than CAV in multiple trials, and oncologists either gave alternating CAV and platinum/etoposide (or PE, as it is abbreviated), or PE alone. About 50-70% of patients had a significant reponse (shrinkage of the cancer volume by more than half), and about 10% had a complete response, with no evidence of disease after usually 6 cycles of treatment. We now have seen that in many lung cancer settings, 4 cycles works as well as more, but historically we have gone up to 6 cycles. Unfortunately, even after a good or great response, the cancer almost always returns, and it is often much less responsive to treatment the second time around, or later. "Maintenance" therapy with longer-term chemo after the first 4-6 cycles has led to a somewhat longer time before the cancer returns, but it has not yet led to any improvement in how long patients live, which is the biggest goal for most patients and oncologists.

More than a decade later, platinum and etoposide is still arguably the best way to treat ED-SCLC. Carboplatin, a newer chemo agent related to cisplatin but with less risk of kidney damage, nausea/vomiting, nerve damage (peripheral neuropathy), and hearing damage (ototoxicity), is often substituted for cisplatin now. There has been one study that compared cisplatin/etoposide to carboplatin/etoposide and found no real differences in outcomes, so many oncologists recommend carboplatin instead because of the toxicity benefit (it's possible that it's slightly less effective, but in the setting of disease that can't be cured, significant differences in toxicity/quality of life can be important).

And then an important trial came out of Japan, in which 154 patients with ED-SCLC were randomized to receive cisplatin/etoposide or cisplatin/irinotecan (also known as CPT-11, or camptosar). This trial , subsequently published in the New England Journal of Medicine (NEJM) (Noda abstract here) stopped after an early look at the data, because the group that received cisplatin/irinotecan were doing so much better than the cisplatin/etoposide arm that it was considered unethical to give cisplatin/etoposide in Japan after that. The curves are shown here, and you can see clear differences between the two arms that show better survival with the newer combination:

(click to enlarge)

The toxicity profiles were different between the two arms, with more issues of low blood counts in the platinum/etoposide arm, and more diarrhea with platinum/irinotecan (diarrhea is consistently the leading major problem with irinotecan), but neither arm was clearly more toxic. So this trial led to cisplatin and irinotecan becoming the standard of care for patients with ED-SCLC in Japan.

So is cisplatin and irinotecan the new standard of care in the US? It's certainly a reasonable option. Studies that get published in the NEJM are meant to reach a broad audience and potentially change standard practice. And in the US and otherwise outside of Japan this became a strong consideration, but it hasn't yet been adopted as the clear best choice for first-line treatment in ED-SCLC. This isn't because the data from Japan aren't high quality (this is a very good oncology group that performed a well-conducted trial), but a recognition that this was still a trial with just over 150 patients, and more importantly that results in Japan can be different from results in the US or other places. First, the oncologists in Japan had more experience with irinotecan than US oncologists, as the drug was developed there. We tend to do better with drugs that we have good experience with, such as by recognizing and managing side effects more effectively. But the second and likely more important point is that irinotecan may behave differently in the more genetically homogeneous Japanese population than in a more diverse and largely European-descended US population. In fact, the toxicities of irinotecan are very significantly affected by the metabolism of irinotecan in the liver, and the proportion of people with a genetic profile predicting for toxicity problems from these liver enzymes is likely to be very low in a Japanese population but considerably higher in other populations. So it is probably worth confirming the Japanese results in other parts of the world.

Two major clinical trials were launched, and we only have the results from one of these. An industry-sponsored trial by the makers of irinotecan (then Pharmacia, now Pfizer) did a US-based trial of cisplatin/etoposide vs. cisplatin/irinotecan with a different schedule (lower dose cisplatin for two weeks out of three, with a lower dose of irinotecan on the same two of three week schedule), and this showed no benefit for cisplatin/irinotecan. The results (abstract by Hanna and colleagues here) were pretty much the same between the two approaches, so it's not as if the irinotecan was a bad choice, but it didn't look clearly superior to our old standard. But we don't know if that is because cisplatin/irinotecan is really no better, or whether tinkering with the dose and schedule is the reason there was no difference.

The second trial is being run by the Southwest Oncology Group (SWOG) and is essentially an exact version of the Noda Japanese trial on a larger scale, with over 600 patients. We don't have any results from that trial (known as SWOG 0124) yet, but we should be getting information on it within the next year or two. If this trial is positive and shows a survival benefit for cisplatin/irinotecan, it will almost certainly establish this combination as the new standard of care in the US as well as Japan, and we will no longer debate whether we have made any real progress in SCLC in the last 10-15 years.