SLIDES & TRANSCRIPTS
Wednesday, June 20

CHEMOTHERAPY/ALTERNATIVE DELIVERY METHODS SECTION - CHEMOTHERAPY IN EARLY LUNG CANCER

Katherine Pisters, MD

I have arbitrarily defined that as up to Stage IIIA disease which is I think the most common definition although some folks might stretch the limit here and, also, include patients with Stage IIIB disease and hopefully the survival figures are very familiar to all of you in this room with our best "early stage" patients have a 5-year survival rate of 67%, and that is obviously plummeting with increasing T and nodal staging.

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So, given the poor survival rate seen following surgical resection alone for these patients with, "early stage" disease and the fact that most of them develop disseminated disease following surgery, clinical trials have looked at chemotherapy and radiation given either after or before surgery.

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I will briefly summarize postoperative radiation therapy with apologies to the radiation oncologists in the room. I think from the lung cancer study group trials we have learned that postoperative radiation does improve local control but does not benefit overall survival. In the Lancet in 1998, the postoperative radiotherapy meta-analysis was published which included data from nine trials over several decades with slightly more than 2,000 patients. The conclusion of this study was that there was an increased risk of death associated with the use of postoperative chemotherapy particularly in patients with early stage disease. However, we must remember that many of the techniques used in the trials in this meta-analysis really had outdated methods.

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This rather busy slide reviews the randomized trials of postoperative chemotherapy alone when compared generally to no postoperative treatment or in one lung cancer study group trial immune modulator of BCG and levamisole. Most of the trials have enrolled somewhere between one and three or four hundred patients, not large trials, and the vast majority of trials have not shown a survival benefit even with the use of cisplatin based regimens. Exceptions to this rule are the two trials that looked at the use of oral UFT. UFT is uracil and tegafur and is a 5-FU derivative which has been studied in two trials in Japan where it was given for a prolonged period after surgery. The initial trial which was published in the European Journal of Surgical Oncology did not report a survival benefit but had a major imbalance in randomization and when they re-analyzed their results they did find a significant survival benefit associated with the use of UFT. The second trial which was published by Dr. Wada and colleagues in the Journal of Clinical Oncology did report a 10 to 15% survival benefit associated with the use of UFT, and finally this year at ASCO Joan Schiller had the pleasure of critiquing the trial ubenimex versus placebo which was a 400-patient randomized trial in completely resected stage I squamous tumors. Ubenimex is an immune adjuvant I guess would be the shortest way to describe it and clearly that data needs to be confirmed.

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The meta-analysis that was published in 1995, in the British Medical Journal looked at the role of chemotherapy in the treatment of non-small cell lung cancer in general and looked at adjuvant trials using chemotherapy and also, adjuvant trials using chemotherapy and radiation. They divided the trials into three general categories, those trials using alkylating agents, those trials with cisplatin-based regimens and then other drugs. The use of alkylating agents was associated with a 15% increase in the risk of death at 5 years or a decrement of 5% in 5 years, a difference that was very significant. The use of platinum-based regimens was associated with a 13% reduction in the risk of death or a 5% improvement in overall survival, a P value that did not achieve statistical significance at 0.08 and finally other drugs which included UFT was associated with an 11% reduction of the risk of death or an absolute difference of 4% with a P value of 0.3 reflecting small numbers of patients that were studied.

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. I want to talk about the UFT trial which is co-chaired by David Harpole and myself and will be run through the American College of Surgery Oncology Group. This trial has the dubious honor of being the first trial that made it through the CEP committee.

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The background to this study is that there are two positive UFT trials from Japan which I mentioned earlier. UFT is a well-tolerated oral agent. Data from the Wada trial reflects some possible chemopreventive effects and, also, data that was presented at AACR in 1999, found some antiangiogenic properties associated with this agent.

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The objectives of this trial are to assess overall survival versus placebo in patients with completely resected Stage I disease, to compare disease-free survival toxicities, patterns of recurrence and also, there will be some translational research correlating angiogenesis and thymidylate synthetase expression with outcome.

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To be eligible for this study patients need to have completely resected T1 to T2, N0 non-small cell lung cancer. We decided to include only those patients whose primary tumors were greater than a centimeter. The primary objective of this trial is survival, and we felt that those patients whose primary tumors were less than a centimeter which is of course the subject of this meeting are more at risk for second primary tumors and would be more appropriately treated on the selenium trial. Patients need to have at least a lobectomy and some assessment of their mediastinal lymph nodes and should be randomized within 4 to 12 weeks of surgery which is in contrast to the selenium trial where patients have up to 3 years postoperatively for enrollment. They need good performance status and adequate blood and liver parameters.

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Patients will be randomized to 300 milligrams per meter squared per day of UFT given on a twice daily schedule along with a fixed dose of leucovorin 30 milligrams twice a day. The control arm will receive placebo, where they will take a placebo/UFT and placebo/leucovorin and to mimic the Wada study they will take drug for approximately a year with 10 5-week cycles.

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The statistical considerations are shown here. We have assumed a 65% survival in the control arm allowing for both T1 and T2 patients with a T1 being a more popular or a more common presentation than T2. There was extensive discussion about what was an important survival benefit to detect, and we finally decided that we wanted to decrease the death hazard ratio by 25% which corresponds to a 7% absolute difference in 5-year survival from 65 to 72%. Allowing adequate power and accrual this translates to a study of 1440 patients.Dr. Ruckdeschel thinks that we are on drugs, thinking that we will be able to accrue this, but the thoracic surgical community has promised me that they do feel this is a realistic goal.

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So, to summarize postoperative chemotherapy I think to date no survival benefit has been demonstrated. Perhaps this is a problem related to drug delivery. In general you are only able to give two or two and one-half cycles of postoperative cisplatin-based regimens. Maybe the drugs themselves that we have studied aren't adequate or maybe we have a numbers problem where we just haven't studied enough patients, and the P value will become significant. Further data is pending from the NCI JBR10 trial as well as several ongoing randomized trials in Europe employing cisplatin-based regimens.

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This slide summarizes the Phase III trial which has compared postoperative chemotherapy and radiation to postoperative radiation and in general has enrolled patients with more advanced stage III disease, not IIIB but IIIA whereas many of the other trials enrolled patients with stage I and II disease. All of these trials from the LCSG at Memorial, the ECOG trial written up by Dr. Keller in the New England Journal and then this year at ASCO a German trial have not found a survival benefit associated with the use of chemotherapy and radiation when compared to radiation therapy alone. I think Dr. Bunn made a comment about this trial last night stating that there had been a survival benefit. Actually that survival difference was not statistically significant although I believe there was a 7-month improvement in median survival.

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The meta-analysis also looked at trials in these categories; again, the use of alkylating agents was associated with a 35% increase in the risk of death at 5 years or an absolute decrease of 7%. P value did not reach statistical significance because of the numbers of patients in these categories and cisplatin-based regimens were associated with only a 6% decrease in the risk of death or an absolute benefit of 2% at 5 years, again, a non-significant P value.

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So, to summarize postoperative chemotherapy and radiation there has been no survival benefit demonstrated when compared to postoperative radiation alone.

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So, to conclude about postoperative adjuvant therapy in resected non-small cell lung cancer there has been no clear survival benefit demonstrated with the use of postoperative radiation, postoperative chemotherapy or postoperative chemotherapy and radiation. The most optimistic thing we could say is that from the meta-analysis is that the use of cisplatin-based regimens was associated with a 5% absolute benefit in 5-year survival or a 13% reduction in hazard ratio with a P value of 0.08. Some people use that as reason to give postoperative chemotherapy and others use it as a reason not to give postoperative chemotherapy. Additional data is pending as I mentioned earlier.

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Now, to talk about preoperative chemotherapy I think there are two randomized trials that are often referred to, one by Dr. Roth and colleagues from M.D. Anderson where patients received cyclophosphamide, etoposide and cisplatin pre- and postoperatively, and a second trial published around the same time by Raphael Rosel and colleagues from Barcelona where patients were randomized to mitomycin, ifosfamide and cisplatin for 2 or 4 cycles prior to surgery versus surgery only. Both of these trials were stopped early after 60 patients had been accrued when interim analyses revealed a significant treatment effect favoring the use of preoperative chemotherapy and long-term follow-up with 5-year survival rates both favoring the use of preoperative chemotherapy.

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Based on that and the fact that the adjuvant trials have been negative we designed a multi-institutional trial looking at the use of preoperative chemotherapy in patients with earlier stages of disease, stage T2 and N0 through T3 and N1, and the trial design gave patients paclitaxel and carboplatin for two cycles prior to surgery and then a planned additional three cycles after surgery.

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This Phase II trial is the basis for the SWOG 9900 trial. The overall survival curve is shown here. The yellow line is the initial cohort of 94 patients and the white line is the second cohort of 40 patients who received three preoperative cycles and two postoperative cycles, and the survival from this is encouraging. The median survival has not been reached to date and when compared to the only historical data that we really can compare it to which is the Mountain literature it appears to be quite promising.

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However, we do need this randomized trial, and I would encourage all of you to accrue patients if possible. This is the SWOG 9900 trial and is an Intergroup trial which you can have access to through SWOG, ECOG, North Central, RTOG and now the American College of Surgery Oncology Group. Only the CALGB has not joined in. This is a 600-patient trial with clinical stage T2 and N0 through T3 and N1 and patients are randomized to receive three cycles of paclitaxel and carboplatin followed by surgery versus surgery alone. To date I believe about 110 or 120 patients have been accrued.

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The only other trial in the literature looking at preoperative chemotherapy in quote, early stage disease is a trial reported by Dr. Depierre from France which was presented at ASCO in 1999. In this trial clinical stage IB through IIIA patients were randomized to mitomycin, ifosfamide and cisplatin followed by surgery versus surgery only. The median survival was improved by 10 months from 26 to 36 months, but at the time of that presentation the P value was not significant at 0.11. The 3-year survival rates, also, trended towards the chemotherapy arm but again we don't have mature results of that study.

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So, to conclude about preoperative chemotherapy I believe the randomized trials in stage III disease are positive. I think preoperative chemotherapy is better tolerated and perhaps more efficacious than postoperative therapy and I think we need to await the results of the Phase III SWOG 9900 trial and the mature results from the French trial before we routinely use preoperative chemotherapy in patients with early stage disease, and that is it.

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[Discussion not transcribed]

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