Lung Cancer Update 2006 (3)

DR HANNA: The Japanese Cooperative Oncology Group (JCOG) reported a positive Phase III study in small cell lung cancer (SCLC) four years ago evaluating the combination of irinotecan and cisplatin compared to a control arm of etoposide and cisplatin, and the etoposide and cisplatin arm performed as you would expect. The irinotecan arm was statistically superior. The study was meant to accrue approximately 225 patients, but the Data Safety Monitoring Committee stopped the study early, according to the statistical design, based on the positive findings. So only 150 patients were accrued.

We set out to either confirm or refute those data in a largely US patient population. We used cisplatin and etoposide as our control arm. We modified the dose and schedule of the irinotecan arm. Thirty percent of the patients on the JCOG trial never received their day-15 irinotecan. We were hoping to make an every four-week regimen an every three-week regimen, and therefore, you would intensify the dose.

We also sought to take advantage of the synergism between irinotecan and cisplatin, so we split the dose. When you administer cisplatin at its full dose and irinotecan at its full dose, you see quite a bit of nausea and vomiting. So the hope was, by splitting the dose, it would be more tolerable.

I was lucky enough to present the data at ASCO last year. It involved approximately 330 patients. It was a two-to-one randomization. Approximately 220 patients received irinotecan and cisplatin, which represents three times the number of patients who received irinotecan on the JCOG trial. Unfortunately, we weren’t able to replicate the data. The efficacy parameters were all the same. The median survival was approximately nine and a half months to 10 months on both arms. The one-year survival was the same on both. The differences between the regimens were largely in terms of the toxicities. The etoposide arm caused more neutropenia and more neutropenic infection. The irinotecan arm caused more diarrhea and mucositis and dehydration. So it is a trade-off of side effects. You have to think about the individual patient. You have to determine which side-effect profile you should consider for your individual patient.

The Southwest Oncology Group is replicating the JCOG regimen. Both arms of the SWOG-S0124 study are identical to the arms of the JCOG study. It’s a much larger trial than the JCOG trial, larger than our trial, with more than 500 patients. I understand that its accrual is quite good. If it’s a matter of our changing the dose and schedule of the irinotecan arm, and that was why it was not superior, then the Southwest Oncology Group study should show us that.

Lung Cancer Update 2006 (4)

DR THOMAS E STINCHCOMBE: We’re interested in investigating nab paclitaxel in patients with small cell lung cancer. In our Phase I trial, we saw some nice responses in patients who had been previously treated for SCLC. The advantage of the combination of carboplatin and nab paclitaxel for patients with SCLC would be a reduction in febrile neutropenia. Our current regimen of cisplatin/irinotecan is associated with a significant incidence of febrile neutropenia of approximately five percent. If we could administer carboplatin/nab paclitaxel every three weeks, it would be a significant improvement in terms of patient convenience over cisplatin/etoposide or carboplatin/etoposide on days one through three.

Cancer Conference Update 2007 (3)

DR KIM: Brain metastases are a big problem in SCLC. A meta-analysis published in 1998 suggested a decreased risk of brain metastases and an improvement in survival with radiation therapy. This was predominantly in limited-stage SCLC with some extensive-stage small cell disease.

The EORTC study that was presented at ASCO 2007 on the use of prophylactic cranial irradiation (PCI) in extensive-stage SCLC was interesting. I believe we have to take the data with a grain of salt in that they show some proof of concept but, again, we have to tailor the data to our patients in practice. This study focused on extensive-disease SCLC. Four to six cycles of therapy were administered up front. They called this induction therapy but, in fact, it is the routine therapy we administer for extensive disease. The patients, if they experienced any response — and this response was gauged by the investigators or the treating physicians, it was not based on RECIST — were then randomly assigned to receive PCI. The PCI varied between 20 and 30 Gray in a one-week or two-week time frame, or no PCI.

Randomization occurred within five weeks of completing the chemotherapy, and then patients were required to start the PCI within six weeks of completing the chemotherapy.

The primary endpoint was to demonstrate a reduction in risk of developing symptomatic brain metastases, and the key word here is “symptomatic.” That goes with the spirit of the entire study — patients were responding. They may have been symptomatically responding, feeling better. It’s a palliative situation.

There was not a mandated staging of the brain at baseline, which can obviously be quite problematic. We had a list of eligibility criteria, by which the patient had to have one or more of the listed symptoms in order to require an imaging test, either a CT or an MRI. We don’t know what would have happened if they had all undergone imaging — some of those people might have had gross disease already but been asymptomatic.

The numbers were quite positive. The hazard ratio for development of symptomatic metastases was 0.27. It’s nearly a 75 percent reduction, which was a very favorable outcome. One-year survival was approximately double with PCI and was reported as 27 percent versus 13.3 percent. Failure-free survival was 23.4 versus 15.5 percent. And again, some stratification issues that were different regarding the amount of extrathoracic disease and extracranial disease existed in the two cohorts. So I don’t believe, definitively, that we can say one way or another that every patient who responds to chemotherapy should receive PCI. I don’t believe that this is that kind of study. But for providing a proof of principle, it validates the concept that administering PCI to patients with extensive-stage SCLC and good chemotherapy responses may be justifiable.

Lung Cancer Update 2007 (1)

DR BELANI: When you compare SCLC to non-small cell, you don’t see the same patient numbers and morbidity and mortality. But if you compare it to other tumors, then it’s a significant disease. There is not enough research on it. Among all lung cancers, the numbers have dropped from 20 percent to 13 percent. Most of them are being treated in the community because the response rate with standard treatments is high enough that these patients don’t show up for a research study. Therefore, it will be difficult to compare experimental regimens to the standard regimen in the front-line setting. We need to develop select markers for select patients in the second-line and recurrent disease settings and take them to the front-line setting. I believe bevacizumab is one of a class of VEGF-targeted compounds that still should be evaluated in SCLC.

Lung Cancer Update 2007 (2)

DR SCHILLER: ECOG completed a Phase II trial in extensive-stage SCLC, which was platinum/etoposide and bevacizumab. It was a one-arm trial that had only 68 patients. It met its first safety endpoint, and the study itself was completed approximately six months ago. There were no unusual toxicities and, specifically, there was a lack of hemoptysis. We are planning to move forward with the randomized Phase III study of cisplatin/etoposide with or without bevacizumab in extensive-stage disease through ECOG.

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