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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Treatment of Recurrent SCLC: Evidence for Survival Benefit
Sun, 01/07/2007 - 16:31
Author
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

As I mentioned in my introduction to the topic, SCLC is typically sensitive to chemo and radiation initially, but it tends to be considerably less responsive after recurrence. Unfortunately, most SCLC patients, or about 75-80% of patients with LD-SCLC and nearly 100% of patients with ED-SCLC , do subsequently recur. One key theme is that the longer patients go between ending first-line treatment and developing a recurrence, the better they are likely to do with any treatment. Such patients are generally divided into those with "resistant" or "sensitive" disease, depending on whether recurrence occurs before or after a 2-3 month period (some define the break point at 2 months, others at 3). It is felt that since initial chemo effectively treats the sensitive disease, the time before recurrence essentially measures the proportion of sensitive vs. resistant cancer cells. Oncologists have generally found the treatments for resistant SCLC to be minimally effective (fewer than 10% of patients respond), but even for more sensitive SCLC (where response rates can be in the 30-40% range in some trials), we have not had good evidence that patients receive significant benefit compared with the side effects. Many patients are in pretty marginal condition for more treatment, and the benefits have appeared to be modest. Accumulating evidence, however, now supports single-agent chemo, most often with topotecan/Hycamtin, and a just reported trial shows a significant improvement in survival compared to supportive care alone.

Many agents have been shown to have some activity. Oral etoposide, an often well-tolerated, inexpensive, and overall easy treatment, is an older treatment that is often used in patients who have not been on etoposide in first line, or have gone more than at least 3 and preferably more than 6 months since last being treated with it. Several never chemo agents have been studied in the last decade, with response rates as shown in the following table:

SCLC second line options table (click to enlarge)

You can see that the response rates are lower in the second-line setting, but there's activity for all of them. Some of these restricted second-line patients to those who had gone two or three months since last treatment before progressing.

At the top of the list is topotecan, a chemo drug that blocks the activity of an important DNA cut-and-repair enzyme that is required to maintain normal cell function, and it preferentially kills faster growing cells in the body, like cancer cells. Topotecan was studied as a single-drug regimen (given daily IV for the first 5 days every 3 weeks) in 92 patients with progressing SCLC (abstract here), half within less than three months of last treatment ("resistant disease"), and half with later progression ("sensitive disease"). The response rate was 6.4% in those with resistant disease, but a very encouraging 37.8% for the sensitive group. The side effects were primarily limited to low blood counts and secondary effects of that, such a fatigue. A larger trial (abstract here) compared this same topotecan regimen to an older combination regimen known as CAV (cyclophosphamide, adriamycin, vincristine) in 211 patients with sensitive disease (defined in this trial as more than 60 days between last chemo and progression):

von Pawel CAV vs. topo trial

This trial demonstrated no significant differences in terms of response or survival, or even notable differences in side effects between topotecan and CAV; however, topotecan improvement lung cancer symptoms across the board, with sigificant improvements (noted in yellow on the symptom table) for many variables:

SCLC von Pawel efficacy and Sx improvement tables

It was on the basis of symptom improvement that the IV topotecan was approved by the US FDA for recurrent SCLC patients with sensitive disease several years ago. However, there was no clear evidence that it improved survival compared to supportive care (the comparison was to another chemo treatment, which is only modestly helpful at best). And oncologists everywhere found that it was remarkably hard to give this chemo at the dose and schedule in which it was approved, as patients often seemed to develop severe and potentially dangerous drops in blood counts. Finally, the schedule of 5 straight days of IV chemo was quite inconvenient for many patients, in light of the difficulty of the treatment and the open questions of whether it really provided much benefit. Instead, most oncologists dropped the daily dose, gave only three days instead of five, or switched to a less studied but more feasible weekly schedule.

Just last month, another trial with topotecan was published (abstract here), this time comparing an oral form of topotecan given for the first five days of a 21 day cycle to supportive care alone for patients with recurrent SCLC (not restricted by time to recurrence). This is the kind of trial that is essentially impossible to do in the US, because patients and physicians don't want to accept randomization between active treatment and no active treatment. Even in the UK, where the trial was based, this ended up being impossible to complete with more than 200 patients as planned. Instead, it had very slow enrollment, and the investigators closed it with 141 patients in total. Even with that rather small trial, there was a significant improvement in survival with oral topotecan compared with supportive care alone (median survival 26 vs. 14 weeks). The response rate was a meager 7%, and another 44% had stable disease for at least a couple of months. As with IV topotecan, the side effects were primarily low blood counts: 6% of patients receiving topotecan died from the treatment. Importantly, quality of life was better on topotecan than supportive care alone, so patients weren't forced to trade between living longer and feeling better. It was interesting to see that the benefit of topotecan was present, and actually greater compared to supportive care alone, in the subset of patients with resistant, earlier recurring disease.

Oral topotecan is not yet approved for commercial use, but I would expect it to become available soon as an alternative to the IV form. In the meantime, this work provides some evidence, albeit in a small trial, for a survival benefit of second-line treatment in recurrent SCLC. This trial was quite unusual in showing a benefit in patients with early recurrence, resistant disease, and this may be a fluke in a small trial, or it may be something we see again in future trials. In the meantime, it's encouraging to see any positive trials in SCLC. What we would really welcome, though, are new agents to offer something beyond a new formulation of a chemo drug we already have. In the next couple of weeks I'll describe some of the other approaches and novel agents that have been in recent clinical trials in SCLC.

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