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ASCO 2001: CRITICAL COMMENTARIES PART 2 |
Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
Correspondence: Thomas J. Lynch, Jr., M.D., Massachusetts General Hospital Cancer Center, 100 Blossom Street, Room 201 Cox, Boston, Massachusetts 02114, USA. Telephone: 617-724-1136; Fax: 617-724-1137; e-mail: tlynch{at}partners.org
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ABSTRACT |
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 Top Abstract Selected Randomized Trials in...Study Design and ResultsReferences |
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While we appear to have reached a plateau in what we can accomplish with various combinations of cytotoxic chemotherapy in metastatic NSCLC, in locally-advanced disease new chemotherapy combinations can achieve remarkable results when combined with radiation therapy. The Southwest Oncology Group presented unprecedented phase II data on the use of cisplatin and etoposide with concurrent radiation therapy followed by consolidation docetaxel in patients with stage IIIB NSCLC.
Key Words. Non-small cell lung cancer • Metastatic disease • Treatment • Stage IIIB NSCLC
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SELECTED RANDOMIZED TRIALS IN ADVANCED LUNG CANCER |
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TopAbstractSelected Randomized Trials in...Study Design and ResultsReferences |
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An EORTC Randomized Phase III Trial of Three Chemotherapy Regimens in Advanced Non-Small Cell Lung Cancer (NSCLC). JP Van Meerbeeck, EF Smit, P Lianes, F Schramel, M Lenz, C Debruyne, G Giaccone (ABSTRACT 1228).
Cisplatin/Gemcitabine (CG) versus Cisplatin/Gemcitabine/Vinorelbine (CGV) versus Sequential Doublets of Gemcitabine/Vinorelbine Followed by Ifosfamide/ Vinorelbine (GV/IV) in Advanced Non-Small Cell Lung Cancer (NSCLC): Results of a Spanish Lung Cancer Group Phase III Trial (GEPC/98-02). V Alberola, C Camps, M Provencia, D Isla, R Rosell, C Vadell, I Bover, A Ruiz Casado, P Azagra, U Jiménez, J González-Larriba, F Cardenal, A Artal, A Carrato, S Morales, J Sánchez (ABSTRACT 1229).
A Multicenter, Randomized Phase III Study of Docetaxel + Cisplatin (DC) and Docetaxel + Carboplatin (DCB) Versus Vinorelbine + Cisplatin (VC) in Chemotherapy-Naïve Patients with Advanced and Metastatic Non-Small Cell Lung Cancer. J Rodriguez, J Pawel, A Pluzanska, V Gorbounova, F Fossella, E Kaukel, K Mattson, M Millward, YS Kim, F Gamza, J Berille, CP Belani (ABSTRACT 1252).
Study Design and Results: Abstract 1227
The Italian Lung Cancer Study Group randomized 612 chemotherapy-naïve patients with stage IV or poor-prognosis IIIB (pleural effusion or N3 supraclavicular) non-small cell lung cancer to one of three treatment arms outlined in Table 1
[1]. Cisplatin/vinorelbine was the reference regimen with which the other two arms were compared. The results are listed in Table 2. There were no statistically significant differences in response rate, survival, or time to progression among the two experimental arms and the reference arm. Toxicity profiles were different with more neutropenia, nausea, and vomiting in the cisplatin/vinorelbine group and more thrombocytopenia in the cisplatin/gemcitabine and cisplatin/paclitaxel arms.
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[2]. Results are presented in Table 4. The patients treated with cisplatin and gemcitabine did not experience a statistically significant difference in survival when compared with the reference regimen of cisplatin and paclitaxel. There was, however, a trend for poorer survival in the nonplatinum arm (p = 0.09). Again there was increased thrombocytopenia in the gemcitabine-containing arm.
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[3]. The 562 eligible patients had stage IV or IIIB (pleural effusion) NSCLC. Results are presented in Table 6. Overall survival was not statistically different in the two experimental arms relative to the reference arm. The response rate was significantly lower in the sequential doublet arm, which did not include a platinum agent. There was a suggestion of increased toxicity in the three-drug regimen while toxicity was lower in the nonplatinum-containing arm. There did not appear to be any additional benefit to the triplet compared with the doublet.
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[4]. The 1,220 enrolled patients came from 139 sites in 28 countries. Results are presented in Table 8. The patients receiving cisplatin and docetaxel had an improved survival when compared with the patients treated with the reference regimen of cisplatin and vinorelbine, while the arm treated with carboplatin and docetaxel did not have an improved survival. The survival benefits observed in the cisplatin/docetaxel arm were not large; patients in that treatment arm lived 0.9 months longer and 5% more people were alive at 1 year than in the cisplatin/vinorelbine arm. The p value for the difference in survival benefit was 0.047.
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This year's ASCO meeting repeated the run of large, negative randomized comparison trials of various chemotherapeutic regimens in advanced NSCLC. The Italian study confirmed the findings of the SWOG and ECOG studies by demonstrating equivalent survival for the cisplatin/gemcitabine and carboplatin/paclitaxel regimens relative to cisplatin/vinorelbine. The toxicities of the regimens differ; cisplatin/gemcitabine causes more thrombocytopenia than cisplatin/vinorelbine, but less neutropenia and less nausea and vomiting. Carboplatin/paclitaxel also causes less nausea and vomiting and neutropenia, but causes more alopecia and neuropathy.
Platinum agents account for a great deal of the toxicity of modern chemotherapy regimens. Are they necessary? A study by Le Chevalier and colleagues found that patients treated with vinorelbine alone had a poorer survival than those treated with vinorelbine and cisplatin [8]. However, if patients are treated with two active nonplatinum agents rather than one, perhaps it is not necessary that one of those agents be a platinum compound. This was the rationale behind the EORTC study. A reference regimen of cisplatin and paclitaxel was compared with cisplatin and gemcitabine as well as to the nonplatinum-containing regimen of paclitaxel and gemcitabine. While there was no statistically significant difference in survival in either of the two experimental arms, there was a trend toward poorer survival for patients in the paclitaxel/gemcitabine arm, and the median survival for these patients was only 6.9 months.
The Spanish Lung Cancer Trial also tried to abolish the platinum, this time with a strategy of sequential doublets (gemcitabine/vinorelbine followed by ifosfamide/vinorelbine). They also tried to increase the intensity of treatment with triplet chemotherapy (cisplatin, gemcitabine, and vinorelbine). As expected, the nonplatinum arm had the best toxicity profile. It also had a significantly lower response rate, though overall survival was not significantly different. There was the suggestion of increased toxicity in the triplet chemotherapy arm but without any apparent benefit in response rate or survival.
Both the Spanish and the EORTC studies suggest that it is too early to abandon platinum in the treatment of advanced NSCLC. Neither study showed a statistically poorer survival in the patients who did not receive platinum. However, the lower response rate seen in the Spanish study and the trend toward poorer survival in the EORTC trial are of concern as neither study may have had the statistical power to detect a survival difference. The EORTC study, for example, was statistically powered to detect a 50% difference in overall survival between the comparison regimens.
As one of the largest randomized trials ever conducted in NSCLC, the TAX326 trial did have the statistical power to detect very small differences in overall survival. That may have been exactly what it accomplished by finding that patients treated with cisplatin and docetaxel lived a statistically significant 0.9 months longer than patients treated with cisplatin and vinorelbine. The p value for the survival difference was 0.047, meaning that there is a 4.7% (approximately 1 in 20) probability that this finding is due to chance alone. This year's ASCO included nine other statistically negative comparisons of chemotherapy (the above trials described as well as the Multicenter Italian Lung Cancer in the Elderly Study in the elderly that found no survival difference between the combination of gemcitabine and vinorelbine versus each agent alone). Add this to the other large comparison studies previously described (ECOG 1594 and SWOG 9509) and that brings us up to 14 comparisons. Using a p value of 0.05, there is a 51% probability (1-0.9514) that at least one of them would be positive by chance alone.
However, 0.05 is the p value we usually accept as significant, and this level of significance relative to a reference regimen has been attained only by the docetaxel/cisplatin combination. Does this result make sense given what we know about NSCLC? Perhaps. Docetaxel in the second-line setting resulted in a superior response rate and 1-year survival relative to vinorelbine (or ifosfamide) in the second-line setting [9]. While TAX326 was not designed to compare cisplatin/docetaxel directly with carboplatin/docetaxel, the fact that the former demonstrated a survival benefit relative to cisplatin/vinorelbine while the latter did not implies that cisplatin may be superior to carboplatin in NSCLC. A preliminary analysis of the Pan-European study directly comparing cisplatin/paclitaxel with carboplatin/paclitaxel suggested a survival benefit to the cisplatin arm but these data have not been updated [10]. ECOG 1594, however, did not show a benefit to cisplatin and paclitaxel over carboplatin and paclitaxel, nor was there a superior survival for cisplatin and docetaxel. The paclitaxel with cisplatin versus carboplatin was not a truly direct comparison: the paclitaxel was infused over 24 hours when given with cisplatin and over 3 hours when given with carboplatin.
Thus the jury is out on what the best regimen is for NSCLC. It is reasonable to conclude at this point that paclitaxel-, docetaxel-, vinorelbine-, and gemcitabine-based regimens are all roughly equivalent in the treatment of advanced NSCLC. This year's ASCO was, in a sense, a victory for platinum in NSCLC. We cannot conclude that regimens without platinum are as good as those with platinum, and the type of platinum may make a difference. The survival benefit of cisplatin over carboplatin, if it is indeed real, is likely quite small in the metastatic setting. However, this could be very important in the locally advanced setting where any increase in efficacy may increase the number of patients who achieve cure. One result of this year's ASCO may be an increased use of cisplatin in stage III NSCLC. The current SWOG study in stage IIIB NSCLC involves the use of a cisplatin/VP-16/radiation concurrent regimen whereas the current Cancer and Leukemia Group B (CALGB) trial uses a carboplatin/paclitaxel/radiation concurrent regimen.
Duration of Therapy in Stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC): A Multi-Institutional Phase III Trial. MA Socinski, M Kies, MJ Schell, KM Bakri, JM Lee, MT Tynan, A Peterman (ABSTRACT 1232).
Study Design and Results
Two hundred and thirty patients with stage IIIB/IV NSCLC were randomized to receive either four cycles of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks (arm A) or identical doses of carboplatin and paclitaxel given every 3 weeks until progression (arm B) [11]. In both arms, patients received weekly paclitaxel 80 mg/m2 at progression.
The patients in arm B received between 0 and 15 cycles of chemotherapy, but the median number of cycles received in both groups was 4, and 42% of the patients in arm B received 4 cycles. There were no statistically significant differences in the receipt of second-line chemotherapy between the two groups with 41% of the patients in arm A and 36% of the patients in arm B going on to receive weekly paclitaxel. There were no differences between the two arms in response rate (21%) or overall survival (median survival 7.8 months, 1-year survival 32%, 2-year survival 15%). Neuropathy did increase with increasing cycles; 15% of the patients in arm B had grade 2-4 neuropathy at cycle 4, while 40% had grade 2-4 neuropathy by cycle 8. The response rate to second-line weekly paclitaxel was 8% in both groups.
Commentary
There have been various strategies used to determine the number of chemotherapy cycles for advanced NSCLC: treat until progression, treat for two cycles beyond maximal response, or treat for a defined number of cycles, usually six to eight. Historically, most studies have found that the median number of cycles received by patients with advanced NSCLC is four regardless of treatment strategy because of disease progression or the patient's inability to tolerate further chemotherapy. We have not had good evidence with which to determine the ideal number of cycles of chemotherapy. In the Socinski trial, patients were randomly assigned to one of two treatment strategies: chemotherapy until progression or simply four cycles. Even in the treat-until-progression arm, the median number of cycles was four, and 42% of the patients received four cycles. While there was no benefit in survival for the patients in the treat-until-progression arm, these patients did experience increased toxicity. Therefore, four cycles of chemotherapy followed by second-line chemotherapy at progression is a reasonable treatment strategy in advanced NSCLC.
Phase I/II Trial of ISIS 3521, an Antisense Inhibitor of PKC-Alpha, with Carboplatin and Paclitaxel in Non-Small Cell Lung Cancer. A Yuen, J Halsey, G Fisher, R Advani, M Moore, M Saleh, P Ritch, G Harker, F Ahmed, C Jones, J Polikoff, W Keiser, T Kwoh, J Holmlund, A Dorr, B Sikic (ABSTRACT 1234).
Study Design and Results
ISIS 3521 is an antisense oligonucleotide of protein kinase C-alpha. In a phase I study of ISIS 3521 given in conjunction with carboplatin and paclitaxel, there was no dose-limiting toxicity of the ISIS compound, and the combination showed efficacy in patients with NSCLC [12]. A phase II trial followed in which patients with previously untreated, advanced NSCLC were treated with ISIS 3521 via continuous infusion 2.0 mg/kg/day on days 1-14, and paclitaxel (175 mg/m2) and carboplatin (AUC 6) given on day 4. Cycles were repeated every 21 days, and 53 patients with NSCLC were treated. The most common grade 3/4 toxicities were neutropenia (26%/43%) and thrombocytopenia (21%/11%). The overall response rate was 46% with one patient experiencing a complete response and 21 patients experiencing partial responses. The overall median survival was 15.9 months, median time to progression was 6.3 months, and 1-year survival exceeded 50%.
A Phase II Trial of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor OSI-774, Following Platinum-Based Chemotherapy, in Patients (pts) with Advanced, EGFR-Expressing, Non-Small Cell Lung Cancer (NSCLC). R Perez-Soler, A Chachoua, M Huberman, D Karp, J Rigas, L Hammond, E Rowinsky, G Preston, KJ Ferrante, LF Allen, PI Nadler, P Bonomi (ABSTRACT 1235).
Study Design and Results
OSI-774 is an oral small molecule inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Dr. Perez-Soler presented a phase II study of OSI-774 in previously treated patients with stage IIIB/IV NSCLC [13]. All patients received prior platinum-based chemotherapy (82% had received more than one prior regimen), and all had 
10% of tumor cells expressing EGFR. Fifty-six patients were treated with OSI-774 150 mg daily. Of note, more than 60% of these patients had been diagnosed more than a year previously. The most common toxicity was an acneiform rash seen in 50% of patients; 32% of patients experienced diarrhea. The overall response rate in this heavily pretreated population was 12.3%. All responders experienced a rash. The median survival was 8.6 months, and 1-year survival rate was 48%.
Commentary
Biologic agents like ISIS 3521 and OSI-774 are the result of decades of effort to better understand the biology of cancer and develop rationally targeted therapies. ISIS 3521 is an antisense oligonucleotide. It specifically binds to the mRNA of protein kinase C-alpha and thereby inhibits gene expression. Protein kinase C-alpha is a cytoplasmic kinase felt to contribute to tumor development by eliciting signal transduction in response to growth factors. OSI-774 is a small molecule inhibitor of the EGFR tyrosine kinase. EGFR is overexpressed in most cases of NSCLC and in other epithelial cancers. Inhibitors of EGFR include ZD1839 (Iressa) and the monoclonal antibody C225.
Unlike standard cytotoxic agents, biologic agents specifically target growth mechanisms utilized by tumor cells rather than normal cells. Because of this, systemic toxicity is decreased, and the toxicities that do exist tend not to overlap with standard cytotoxic agents. In the above phase II trials, both ISIS 3521 and OSI-774 were very well tolerated. The excellent survival data were especially refreshing following the presentations of the large phase III trials; the median survival in both studies exceeded one year, and in the OSI-774 study, this was achieved in previously treated patients.
Given the staggering number of patients with advanced NSCLC who present each year, endeavors to determine the very best combination of standard cytotoxic agents are clearly important. However, the stunning consistency in the results of large randomized trials using various combinations of these agents implies that we have maximized their potential. Novel biologic agents offer the best hope for the future of lung cancer therapy. The phase II trials of ISIS 3521 and OSI-774 are promising, but both are subject to the usual criticisms of phase II trials. The patients in these trials, particularly in the OSI-774 trial, represent a select group. Clearly OSI-774 is an active agent in NSCLC, though it is not yet certain where it should fit in our treatment algorithm. Because patients in the ISIS trial also received cytotoxic agents known to be active, it is difficult to know how much of the effect can be attributed to the study compound. Still, it would be wonderful if the average patient with advanced NSCLC had a life expectancy exceeding 1 year. To know whether this is possible, we require more large phase III comparison studies involving these new biologic agents. Such a trial of ISIS 3521 is currently ongoing, and phase III trials of OSI-774 are also planned.
Consolidation Docetaxel Following Concurrent Chemoradiotherapy in Pathologic Stage IIIb Non-Small Cell Lung Cancer (NSCLC) (SWOG 9504): Patterns of Failure and Updated Survival. L Gaspar, D Gandara, K Chansky, KS Albain, PN Lara, Jr, J Crowley, RB Livingston (ABSTRACT 1255).
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STUDY DESIGN AND RESULTS |
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TopAbstractSelected Randomized Trials in...Study Design and ResultsReferences |
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Commentary
In the treatment of stage III NSCLC, chemotherapy and radiation can be curative. However, the overwhelming majority of patients die of their disease. Multiple phase III studies have confirmed improved survival for patients with stage III NSCLC treated with chemotherapy and radiation over radiation alone. More recent studies have indicated that concurrent chemotherapy and radiation is superior to sequential treatment [15, 16]. In phase III trials of chemotherapy and radiation, the median survival is at best 15 months and the 5-year survival is around 15%. Recent phase II studies in stage III NSCLC usually employ trimodality therapy with chemotherapy and radiation followed by surgery. Patients in these studies are obviously highly selected, and frequently these aggressive strategies are limited to better-prognosis IIIa patients. In spite of this, the best median survivals in these studies have been between 20 to 25 months, and the best 5-year survivals have been 31%-37% [17-19]. Therefore, the 27-month median survival and 40% 3-year survival achieved by the patients in SWOG 9504 are extraordinary. Even more amazing is the fact that all of the patients had pathologically staged IIIb disease and none of them had surgery.
Why did the patients in this study do so well? If indeed concurrent chemotherapy and radiation is better than sequential treatment, then one advantage of the SWOG 9504 schedule may be that it includes 12 days in which chemotherapy and radiation overlap. Also, cisplatin and etoposide can be given along with radiation in full doses, thereby providing maximum systemic control in addition to increasing the local tumor's sensitivity to radiation. Does the consolidation docetaxel have an impact? It would appear that it does. The SWOG group had previously studied the identical induction regimen of cisplatin/etoposideand radiation followed by consolidation cisplatin and etoposide in similar IIIb patients. This produced a median survival of only 15 months and a 3-year survival of 17% [14].
There are a few lessons to be learned from SWOG 9504. First, it appears that while varying the combinations of chemotherapy does not have a significant impact in stage IV NSCLC, it may have an impact in stage III disease. Second, if results as seen in SWOG 9504 can be attained in stage IIIb patients without surgery, perhaps surgery should not be a part of the management of stage IIIa patients. This question is being addressed by an ongoing phase III High Priority Intergroup study in which stage IIIa patients are randomized to receive induction cisplatin and etoposide with concurrent radiation followed by either surgery or continuation of radiation to a curative dose; both groups receive consolidation cisplatin and etoposide. Finally, SWOG 9504 teaches us that stage IIIb patients can do quite well. We therefore we have an obligation to treat them with curative intent and to define the precise regimen that can maximize their chance for cure.
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REFERENCES |
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TopAbstractSelected Randomized Trials in...Study Design and ResultsReferences |
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