The Oncologist, Vol. 9, No. 2, 232–238,
April 2004
© 2004 AlphaMed Press
Highlights from the Tenth World Conference on Lung Cancer
Tracey L. Evans
The University of Pennsylvania Medical Center—Presbyterian, Division of Hematology/Oncology, Philadelphia, Pennsylvania, USA
Correspondence:
Tracey L. Evans, M.D., University of Pennsylvania Medical Center—Presbyterian, Division of Hematology/Oncology, Medical Arts Building Suite 103, 39th and Market Street, Philadelphia, Pennsylvania 19104, USA. Telephone: 215-662-8947; Fax: 215-243-3268; e-mail: tracey.evans{at}uphs.upenn.edu
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ABSTRACT
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Should adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC) be the standard of care? That question has been much debated since the presentation of results from the International Adjuvant Lung Cancer Trial (IALT) in May 2003 at the plenary session of the American Society of Clinical Oncology annual meeting. The IALT study showed a statistically significant survival advantage for patients treated with cisplatin-based adjuvant chemotherapy. The topic of adjuvant chemotherapy permeated the Tenth World Conference on Lung Cancer held from August 10–14, 2003 in Vancouver, Canada. Updated results of the IALT study were presented along with results from the Big Lung Trial from the United Kingdom and the Adjuvant Lung Project Italy trial, neither of which showed a significant survival benefit for adjuvant chemotherapy. How to put the IALT data into practice remains controversial, and leading lung cancer experts have not reached a consensus.
Platinum-based doublets that include a taxane, vinorelbine, or gemcitabine remain the standard of care for the first-line treatment of metastatic NSCLC. However, there may soon be a new option for second-line treatment. A randomized study of pemetrexed in the second-line setting found efficacy similar to that of docetaxel given every 3 weeks, with less toxicity.
Gefitinib was recently approved by the U.S. Food and Drug Administration for the treatment of advanced NSCLC following platinum-based chemotherapy and docetaxel. However, concerns have arisen about toxicity due to reports of interstitial pneumonitis from Japan. The observed incidence of interstitial pneumonitis from the data available to date is approximately 1%. Which patients derive the most benefit from gefitinib? It appears that lifetime nonsmokers and patients with bronchioloalveolar histology have the highest probability of disease response.
Key Words. Lung cancer • Adjuvant therapy • Pemetrexed • Gefitinib
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ADJUVANT CHEMOTHERAPY IN NON-SMALL CELL LUNG CANCER
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At the Tenth World Conference on Lung Cancer, LeChevalier et al. reported updated results from the International Adjuvant Lung Cancer Trial (IALT). In that trial, conducted from 1995 to 2000, 1,867 patients from 148 centers in 33 countries were randomized to receive either observation or adjuvant chemotherapy following complete resection of non-small cell lung cancer (NSCLC) [1]. Four different chemotherapy regimens were permitted, which were predetermined by the center at which the patients were treated. These are listed in Table 1
along with the percentage of patients who received each regimen within the chemotherapy arm. Thoracic radiotherapy was optional but was predetermined by nodal stage at each center and was not to exceed 60 Gy. Chemotherapy was administered within 60 days of surgery.
Thirty-five percent of patients in each arm underwent pneumonectomies and the remainder had lobectomies. Thirty-nine percent of patients in each arm had stage III disease (the remainder were stage I or II), and 46% had squamous cell carcinoma. Seventy-four percent of patients received at least 240 mg/m2 of cisplatin; 8% of the patients assigned to the chemotherapy arm received no chemotherapy. The lethal treatment-associated toxicity rate in the chemotherapy arm was 0.8%. The causes of death in those seven patients were marrow aplasia in five, renal failure in one, and hyponatremia in one.
The median overall survival times for patients in the chemotherapy and control arms were 50.8 months and 44.4 months, respectively, and the p value for this survival difference was <0.03 (Table 2). The 5-year overall survival rate in the chemotherapy arm was 44.5%, versus 40.4% in the control arm, an absolute 5-year survival benefit of 4.1%. The overall survival hazard ratio for chemotherapy was 0.86 (95% confidence interval [CI] = 0.76–0.98). The disease-free 5-year survival rate was 39.4% in the chemotherapy arm, versus 34.3% in the observation arm, an absolute benefit of 5.1%, and hazard ratio was 0.83 (95% CI = 0.74–0.94). The benefits of chemotherapy appeared similar across all observed subgroups.
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THE BIG LUNG TRIAL
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Results from the Big Lung Trial (BLT) were reported by Waller and colleagues. In this large, multicenter study in the United Kingdom, all patients with NSCLC received primary therapy as determined by stage (surgery, radiation, or best supportive care) and were, in addition, randomized to receive either three 3-weekly cycles of cisplatin-based chemotherapy (cisplatin/vindesine, mitomycin/ifosfamide/cisplatin, mitomycin/vinblastine/cisplatin, or vinorelbine/cisplatin) or no chemotherapy. In the subgroup of patients receiving best supportive care as their primary modality, there was a statistically significant survival benefit for chemotherapy [2]. The current presentation was limited to the 381 patients who underwent surgery [3]. The arms were well balanced, with 13%–14% of patients receiving postoperative radiation (mostly for positive margins), 83%–84% having complete resections, and 48%–49% with squamous histology. The stages were as follows: stage I, 26%–29%; stage II, 37%–40%; stage IIIa, 25%–27%; and stage IIIb/IV (mostly satellite nodules detected in surgery), 6%–10%.
Sixty-four percent of patients received all three planned cycles of chemotherapy; 16% of the patients assigned to the chemotherapy arm did not receive any chemotherapy, and 13% received only one cycle. There was no benefit to chemotherapy in terms of overall survival or progression-free survival. The overall survival hazard ratio for chemotherapy was 1.02 (95% CI = 0.77–1.35).
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ADJUVANT LUNG PROJECT ITALY
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Scagliotti et al. reported results from the Adjuvant Lung Project Italy (ALPI). In that study, 1,209 patients with completely resected NSCLC were randomly assigned to receive either mitomycin, vindesine, and cisplatin every 3 weeks for three cycles or no chemotherapy [4, 5]. Sixty-nine percent of the patients assigned to the chemotherapy arm received all three cycles. Stage III disease was present in 28%–29% of patients, while the remainder were stage I or stage II. Forty-three percent of patients in each group were scheduled to have postoperative radiation therapy, and fewer in the chemotherapy group were able to complete it (65% versus 82%). There was no significant difference in overall survival between the two groups (hazard ratio = 0.96, 95% CI = 0.81–1.13, p = 0.589) or progression-free survival (hazard ratio = 0.89, 95% CI = 0.76–1.03, p = 0.128).
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COMMENTARY
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Surgical resection of early-stage NSCLC offers patients with this disease the best hope for cure. Unfortunately, only about 50% of patients treated with primary surgical resection are alive 5 years later [6]. Efforts to improve this survival rate have been disappointing. A meta-analysis of postoperative radiation therapy (utilizing primarily outdated techniques) actually showed a survival decrement [7]. Individual randomized trials of adjuvant chemotherapy have been suboptimal due to the use of older, less effective chemotherapy regimens, poor chemotherapy compliance, and insufficient power to detect small benefits. To remedy this latter deficiency, the Non-Small-Cell Lung Cancer Collaborative Group performed a meta-analysis examining the benefit of adjuvant chemotherapy [8]. Seventeen trials were identified that compared surgery and chemotherapy with surgery alone. Taken together, there was a nonsignificant trend toward worse survival in the patients who received chemotherapy due primarily to the studies including alkylating agents, which consistently led to worse survival than with surgery alone (hazard ratio = 1.15, p = 0.005). When the analysis was limited to the eight trials using platinum-based chemotherapy (including a total of 1,394 patients), there was a trend toward better survival in the chemotherapy group that was nearly significant (hazard ratio = 0.87, p = 0.08). This translates into an absolute survival benefit of 5% at 5 years.
The IALT study was designed to have the statistical power to confirm an absolute survival benefit of 5% at 5 years for chemotherapy (from 50% to 55%), and the planned accrual was 3,300. However, the study was closed early due to slow accrual. Nonetheless, at 1,867 patients, the IALT study remains the largest adjuvant trial presented to date. The IALT study was large enough to determine that the very small benefits (a 4.1% greater overall survival rate at 5 years and a 5.1% greater disease-free survival rate) were statistically significant (p values <0.03 and <0.003, respectively). Why was the IALT study positive while the BLT and ALPI were not? Some point to the better compliance with treatment in the IALT study; 74% of the chemotherapy patients in the IALT study received at least 240 mg/m2 of cisplatin. In the BLT and ALPI, 64% and 69% of patients, respectively, received all three chemotherapy cycles. Perhaps, however, these studies are not truly discrepant. As Dr. Richard Stephens, statistician for the BLT pointed out, the 95% confidence intervals of the hazard ratios overlap, so all are in fact consistent with a very small overall survival benefit for chemotherapy (Table 3). The IALT study is the largest of the adjuvant studies and, therefore, may be the only study with the statistical power to detect this small benefit.
There may be a real benefit for adjuvant chemotherapy in NSCLC, but the magnitude of this benefit is likely quite small. Per IALT data, 25 patients must be treated to convert one person who otherwise would have died from the disease into a 5-year survivor; the other 24 patients would be exposed to the toxicities of chemotherapy with no benefit. One of every 125 patients treated experience lethal toxicity with the IALT regimens, and those patients die within 6 months of surgery, whereas patients who die of relapse usually live 1–2 years beyond surgical resection. Oncologists do routinely treat other diseases for which adjuvant chemotherapy has a similar benefit. However, lung cancer patients are not the same as breast cancer or colon cancer patients. Lung cancer patients frequently have significant additional comorbidities that can complicate chemotherapy administration, and the chemotherapeutic regimens are usually more difficult. It must be emphasized that while the IALT study used four different chemotherapy regimens, all of them contained cisplatin. There are absolutely no data supporting the use of adjuvant carboplatin-based therapy, and there is at least some indication that cisplatin may be a better drug than carboplatin in NSCLC [9, 10]. Therefore, any adjuvant chemotherapy administered off study should be cisplatin based.
Based on the totality of the evidence, should adjuvant chemotherapy for resected NSCLC become the standard of care? It depends on whom you ask. Dr. Lawrence Einhorn said he felt that the existing data were sufficient to recommend adjuvant therapy to patients. However, Dr. David Waller and Dr. Giorgio Scagliotti, presenters of the BLT and ALPI, respectively, said they did not believe adjuvant chemotherapy should become standard of care. Dr. Scagliotti stated, "Future adjuvant trials must still include a control arm of surgery alone, and the use of adjuvant therapy should be restricted to clinical trials." However, given the IALT results, accruing patients to trials containing an observation arm may not be feasible in the U.S. How can practicing oncologists wisely advise their patients when the experts cannot agree? Clearly, only the most fit patients should be offered adjuvant chemotherapy. Such patients are then entitled to a detailed explanation of the strength of the data and the magnitude of the benefit for adjuvant chemotherapy. As either choice (to receive adjuvant therapy or not) is reasonable given the current state of the evidence, patient preference must factor strongly in the decision to administer. Enrolling patients in clinical trials remains critical. Ongoing randomized studies evaluating surgery alone versus surgery plus chemotherapy include the Neoadjuvant Taxol Carboplatin Hope (NATCH) trial in Spain, the National Cancer Institute of Canada adjuvant trial, the Adjuvant Navelbine International Trialist Association (ANITA) 1 and ANITA 2 trials, the Cancer and Leukemia Group B (CALGB) 9633 trial, and the Southwest Oncology Group (SWOG) 9900 trial. Time will tell whether these studies provide additional enlightenment or confusion to the adjuvant chemotherapy issue.
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SECOND-LINE CHEMOTHERAPY IN ADVANCED NSCLC
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Second-Line Docetaxel Scheduling
Camps et al. reported results from a Spanish Lung Cancer Group (SLCG) phase III trial in which 259 patients who had received prior chemotherapy for advanced NSCLC were randomized to receive either the traditional method of second-line docetaxel administration (75 mg/m2 every 3 weeks) or a weekly regimen of docetaxel (36 mg/m2 weekly for six consecutive weeks of an 8-week course) [11]. The primary end point was 1-year survival, and secondary end points included overall survival, time to progression, response rate, toxicity profile, and quality of life using the Lung Cancer Symptom Scale (LCSS). While there was a trend toward a higher 1-year survival rate in the every-3-weeks arm (29.2% versus 21.8%), this was not statistically significant (Table 4). The response rates and time to progression rates were also not significantly different between the two arms. However, overall survival was significantly better in the every-3-weeks arm, with median survival times of 7.1 months versus 5.4 months (p = 0.04). While the rates of grade 3/4/5 toxicities were similar in both arms, the toxicity profiles did differ, with more neutropenia, leukopenia, alopecia, and hepatic toxicity in the every-3-weeks arm and more diarrhea, mucositis, and dyspnea in the weekly arm. There was no difference in quality-of-life measurements between the two arms.
Pemetrexed versus Docetaxel
Sheperd et al. reported the results of a study in which 571 previously treated patients with advanced NSCLC were randomized to receive either docetaxel at a dose of 75 mg/m2 or pemetrexed at a dose of 500 mg/m2 (with B12 and folate supplementation) on an every-21-days schedule (Table 5) [12]. The response rates, times to progression, and overall survival rates were similar in the two arms (Table 6). Pemetrexed, technically, just missed statistical noninferiority for overall survival as determined by the initial study design. In addition, there was significantly less toxicity in the pemetrexed arm (Table 7); specifically, neutropenia, fever and neutropenia, neuropathy, and hospitalization rates were lower. Total drug-related serious adverse events were 10% for patients treated with pemetrexed and 24% for patients treated with docetaxel, and this difference was significant.
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COMMENTARY
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It is easy to become lackadaisical about the treatment of metastatic NSCLC. Chemotherapy may be beneficial, but when study after study shows similar first-line efficacy for all modern platinum-based doublets, how could it matter what we choose for first-line, or even second-line, treatment? Could the schedule of chemotherapy possibly make a difference? Shouldn’t we strive to minimize toxicity as efficacy usually remains depressingly the same? This sort of thinking has led to the increasing popularity of weekly chemotherapy. Weekly regimens appear better tolerated, and the assumption has been that they are likely similar in efficacy to the every-3-weeks or every-4-weeks regimens. However, as the Spanish study comparing every-3-weeks docetaxel with weekly docetaxel demonstrates, it is not correct to make such an assumption without randomized comparisons. Technically, the way the study was designed, there was not a difference in efficacy between the two regimens because the primary end point of 1-year survival rate was not significantly different. However, there was a trend toward a higher 1-year survival rate in the every-3-weeks arm, and it is hard to ignore the statistically different overall survival rate favoring the every-3-weeks docetaxel arm, with a 1.7 month longer median survival time and a p value of 0.04. As mentioned, one needs to be very cautious in reaching conclusions regarding secondary end points in small studies. With this caveat, as the measured quality of life and severe toxicities were similar in both arms, the every-3-weeks regimen appears to be the schedule of choice, according to that study. A German study comparing every-3-weeks docetaxel with weekly docetaxel on a schedule of 35 mg/m2 on days 1, 8, and 15 every 4 weeks was also presented [13]. While the weekly schedule in that study also caused less leukopenia, neutropenia, and alopecia, survival and efficacy data are not yet available. Another study presented at the 2003 American Society of Clinical Oncology (ASCO) annual meeting compared second-line docetaxel (75 mg/m2 every 3 weeks) with weekly docetaxel (33.3 mg/m2 weekly for 6 of 8 weeks) and used quality of life as the primary end point [14]. Preliminary results were available on the 220 patients treated as part of that study. There was no difference in global quality of life between the two arms, although there was significantly better cognitive function, cough, and pain in the weekly arm, with less hair loss, neutropenia, and febrile neutropenia. Patients in the every-3-weeks arm had a lower incidence of diarrhea. Overall survival, a secondary end point in that trial, was not significantly different between the two arms of the study. Therefore, while it is not clear that the demonstrated efficacy of weekly docetaxel is sufficient for it to become the new standard of care, this method of administration may be reasonable for patients in whom the toxicity profile of the every-3-weeks schedule is not desirable.
Docetaxel is the only U.S. Food and Drug Administration (FDA)-approved agent for the second-line treatment of advanced NSCLC that has progressed following platinum-based chemotherapy. There will likely soon be a new option. The multitargeted antifolate, pemetrexed, is the first agent shown to improve overall survival in a randomized study of mesothelioma [15]. It now appears that pemetrexed has efficacy similar to that of docetaxel in the second-line treatment of advanced NSCLC. The toxicity profile of pemetrexed is much better than that of the traditional method of docetaxel administration. As demonstrated in the mesothelioma study, vitamin supplementation is critical to minimizing toxicity from pemetrexed.
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GEFITINIB
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Safety and Tolerability
Gefitinib (Iressa®; AstraZeneca Pharmaceuticals; Wilmington, DE) was approved by the FDA in May 2003 for the treatment of advanced NSCLC in the setting of progressive disease following platinum-based chemotherapy and docetaxel. Gefitinib was previously approved for use in Japan. There have been reports of fatal interstitial lung disease in Japanese patients taking gefitinib. Representatives from the manufacturer reviewed the data available on the rate of interstitial lung disease in gefitinib-treated patients [16]. Approximately 37,000 patients have been treated in Japan since the approval of gefitinib. Interstitial pneumonitis has been reported in 2% of these patients, and 0.7% of patients treated with gefitinib experienced fatal pneumonitis. Of the 44,000 patients treated outside Japan, 0.33% developed pneumonitis and 0.1% developed fatal pneumonitis. As part of the expanded access program in the U.S., 24,000 patients received gefitinib prior to its FDA approval. Pneumonitis occurred in 0.36% of patients and fatal pneumonitis occurred in 0.06%. Similar percentages were noted in the expanded access program conducted throughout the rest of the world (14,500 patients), with 0.35% of patients developing pneumonitis and 0.06% developing fatal pneumonitis. Globally, there have been at least 80,000 patients treated with gefitinib; 1% of these patients developed interstitial pneumonitis and 0.37% developed fatal interstitial pneumonitis. Autopsy data from cases of fatal pneumonitis are limited (approximately 3% of cases). In those cases examined, the lungs were characterized by diffuse alveolar damage.
Patient Characteristics
Medical records, pathology reports and specimens, and imaging studies were reviewed for 139 patients treated in one of three gefitinib monotherapy trials at Memorial Sloan-Kettering Cancer Center [17]. Twenty-one of those patients had confirmed radiologic partial responses, and the characteristics of those patients were compared with those of the nonresponders. Analyzed variables included performance status, gender, histology, prior chemotherapy, and smoking history. Specimens from a subpopulation of patients (18 of the responders and >30 nonresponders) were also assessed for epidermal growth factor receptor (EGFR), phosphorylated (p)-EGFR, p-extracellular-signal-regulated kinase (ERK), p-Akt, PTEN, Her-2, p27, p53, and k-Ras status.
In a univariate analysis, bronchioloalveolar (BAC) histology and a history of never smoking were highly predictive of response, and these remained independent predictors in a multivariate analysis. The 11 patients with BAC histology who were never smokers had a response rate of 55% and a median survival time of 14 months. The 38 patients who were either never smokers or had BAC histology had a response rate of 26% and a 9-month median survival time. Patients who were current or former smokers with non-BAC histology had a 6% response rate and 4-month median survival time, and there were no responses observed in patients with nonadenocarcinoma histology. None of the molecular markers were significant predictors of response. Better performance status was predictive of better response rate in the univariate analysis but was not an independent predictor in the multivariate analysis and, while there was a trend toward a superior response rate in women (19% versus 8% in men, p = 0.14), this also did not hold up in the multivariate analysis and is likely the result of greater numbers of women with BAC or who were never smokers.
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COMMENTARY
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Gefitinib is an oral EGFR tyrosine kinase inhibitor that was approved by the U.S. FDA on May 5, 2003. Now that gefitinib is available, how do we use it? It was approved on the basis of the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) 2 study, which showed a response rate of 10.6% and a symptom improvement rate of 40% in patients with advanced NSCLC treated with gefitinib following platinum-based and docetaxel chemotherapy [18]. It is important to remember that there has not been any randomized study demonstrating superior survival rates for patients treated with gefitinib. Gefitinib should not be used along with cytotoxic chemotherapy off study given the results of the two Iressa NSCLC Trial Assessing Combination Treatment (INTACT) trials in which the combination of gefitnib and chemotherapy offered no better efficacy than chemotherapy alone [19].
Interstitial pneumonitis appears to be a real, albeit rare, toxicity of treatment with gefitinib, and for reasons that are not clear, this toxicity may be more common in Japanese patients. Nonetheless, gefitinib remains a remarkably tolerable treatment, and it appears to be safe even in patients with poor performance statuses, a group for whom there has been no satisfactory treatment.
Who is likely to respond to gefitinib? Life-long nonsmokers with BAC appear most likely to respond, and, in the Sloan-Kettering analysis, the response rate observed in nonsmokers with BAC was an impressive 55%. Two studies of EGFR tyrosine kinase inhibitors specifically in BAC are ongoing. Preliminary results of the SWOG 0126 trial, evaluating gefitinib in BAC, were presented at the Tenth World Conference on Lung Cancer in Vancouver. The response rate in previously untreated patients was 19%, while the rate in previously treated patients was 12% [20]. Erlotinib (TarcevaTM; Genentech, Inc.; South San Francisco, CA) is another orally available EGFR tyrosine kinase inhibitor. Preliminary results of an erlotinib trial in BAC were presented at the 2003 ASCO annual meeting. The preliminary response rate observed was 26% [21]. A phase III trial comparing erlotinib with best supportive care as third-line treatment of advanced NSCLC was recently closed to accrual and results should be available shortly.
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Received October 23, 2003;
accepted for publication December 12, 2003.
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Abstract
Adjuvant Chemotherapy in Non...
