After Avastin was found to produce a survival benefit when combined with chemo in advanced NSCLC, it became increasingly appealing to try to see if adding Avastin in earlier stages of lung cancer, both SCLC and NSCLC, where it might increase the cure rate. I've described how it's being studied in a trial with post-operative chemo (prior post here), but another place where it's being studied in the potentially curative setting is locally advanced NSCLC and LD-SCLC. However, a trial of Avastin combined with chemo and radiation for LD-SCLC was actually stopped early due to the appearance of an unusual and serious complication that may be a real problem, leading to a great deal of caution in this line of research.

As described here, a trial in LD-SCLC that combined carboplatin, irinotecan, and avastin with radiation stopped after 29 patients were enrolled, because two confirmed cases of tracheo-esophageal (T-E) fistula (a connection between the trachea (windpipe) and esophagus) were confirmed, of whom one died, and a third patient also died with a suspected but not confirmed T-E fistula. So if there were about 10% of patients with a life-threatening or fatal side effect, that's a red flag, and this led the manufacturers and the FDA to issue a warning about it. The official packaging information will also reflect information on this issue in the future. At least six other cases of T-E fistulas associated with chemo or radiation, have been reported to the company, and others may come as this information becauses available. In the lung cancer conference I co-chair here, my colleagues and I presented a patient who was treated elsewhere and had received prior chemoradiation, then chemo and avastin, and developed an enormous fistula that was sent to our center to manage. Our surgeons noted that this was the largest T-E fistula they had ever seen in their careers, so at our meeting we publicized the case and raised the question to our participants whether thay had seen similar cases (they hadn't). So the closure of that trial didn't come out of left field for me. We suspected that avastin could be related to development of fistulas in patients who received radiation, but one case doesn't make a trend. We're providing details of our case to the company.

Many other trials that include Avastin with concurrent radiation have been halted or are at least being monitored especially closely. One of the higher profile trials that is still being conducted, although it's been stopped and started a few times because of regulatory oversight issues, is SWOG 0533. In this study, Avastin is added to SWOG's standard backbone for locally advanced, unresectable stage III NSCLC (IIIA and IIIB) of cisplatin/etoposide with concurrent radiation, followed by three cycles of consolidation taxotere (described more in a prior post). Because we remain concerned about side effects like bleeding risks for central cancer, and apparently should also be concerned about other things like T-E fistulas, Avastin is being carefully phased in. The first group of patients receives all of the standard chemoradiation and then avastin starting with the taxotere. Provided that this proves safe, the next group receives avastin starting one week after the start of chemoradiation. If this is also safe, the third group receives avastin starting right with the beginning of all of the treatment. Here's a figure to show the design:

(Click to enlarge)

The primary focus of the trial is to assess, as meticulously as possible, the safety of adding avastin to our most common treatment plans. In fact, there are two different groups being tested, one for patients with non-squamous tumors (or <50% if mixed), tumors without cavitation and not near a major blood vessel, and no history of coughing up blood (hemoptysis). The high risk group has one or more of these factors.

If the combination of avastin with chemoradiation proves safe in this trial, it will be possible to move forward with larger trials that look at efficacy (response rate and survival) of these combinations in the locally advanced setting. Importantly, the combination of cisplatin/etoposide/RT is also commonly used for LD-SCLC, so if safety is established in the SWOG 0533 trial, we can use this safety information in SCLC as well (but we'd still want to confirm whether there are any histology-specific risks, since we have seen that squamous has higher risk than non-squamous).

The issue with development of T-E fistulas in an unstudied setting provides another reason to be cautious about the potentially dangerous as well as favorable effects of adding new agents before we know about the safety of these combinations. And the stakes are particualrly high when patients may already be cured with standard treatments.