- Email: [email protected]
Perspectives and opportunities: docetaxel in the current and future treatment of non-small cell lung cancer
Perspectives and Opportunities: Docetaxel in the Current and Future Treatment of Non–Small Cell Lung Cancer Mark R. Green Docetaxel is active as monotherapy in patients with advanced or metastatic non–small cell lung cancer. In addition to the conventional 3-weekly regimen, docetaxel delivered in smaller, weekly doses to patients who are elderly or have comorbidities maintains activity while minimizing myelosuppression. Randomized phase III trials show that docetaxel monotherapy improves survival when compared with best supportive care in both first- and second-line settings. More recently, the combination of docetaxel with cisplatin in chemotherapy-naive patients has been shown to be significantly superior to the vinorelbine/cisplatin combination in terms of both increased survival and reduced toxicity. Docetaxel can be combined with nonplatinum agents such as gemcitabine to produce regimens that have substantial activity and a favorable therapeutic index. In multimodality therapy, following platinum/etoposide chemoradiation with docetaxel may have played an important role in the encouraging outcome of the recent Southwest Oncology Group 9504 study. If this can be confirmed, docetaxel appears suitable for inclusion in a range of sequential chemoradiotherapy approaches. Docetaxel can safely be combined with a platinum in patients receiving thoracic radiotherapy; and the combination is a candidate for induction therapy in patients with stage IB-IIIA disease. There is also considerable promise in combining docetaxel with any of the large number of molecularly targeted therapies now becoming available. Semin Oncol 29 (suppl 12):17-21. Copyright 2002, Elsevier Science (USA). All rights reserved.
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HIS ARTICLE reviews current knowledge about the treatment of non–small cell lung cancer (NSCLC) with docetaxel and assesses possibilities for further progress. DOCETAXEL IN SECOND-LINE THERAPY
Docetaxel is active in the treatment of patients with advanced NSCLC who have failed prior chemotherapy and is the only drug licensed in this setting. In a phase III trial, 75 mg/m2 docetaxel every 3 weeks was shown to improve survival when compared with best supportive care.1 Quality of life was enhanced and use of both palliative radiation and analgesic medication was reduced in the docetaxel group when compared with controls. Moreover, second-line docetaxel at 75 mg/m2 has been shown to improve 1-year survival when compared with an active control regimen of either vinorelbine or ifosfamide.2 Given this background, research interest in second-line therapy is now Seminars in Oncology, Vol 29, No 3, Suppl 12 (June), 2002: pp 17-21
focused on the use of docetaxel in combination with other cytotoxic agents or with novel cytostatics. FIRST-LINE ACTIVITY IN THREE-WEEKLY AND WEEKLY SCHEDULES
When used on an every-3-weeks schedule, docetaxel has substantial first-line activity in NSCLC.3 Pooling data from four phase II studies involving a total of 157 patients shows an overall response rate of 25%, a median survival of 9.9 months, and a 1-year survival rate (based on three studies) of 38%. Collectively, these data show a level of activity for docetaxel that is as high and as consistent as has been achieved with any other single agent in this setting. Furthermore, docetaxel has been proven superior to best supportive care alone in chemotherapy-naive patients with metastatic or non-resectable NSCLC.4 In this phase III trial by Roszkowski et al,4 207 patients were randomized to receive either 100 mg/m2 docetaxel every 3 weeks or best supportive care. Compared with the control arm, patients assigned to docetaxel had significantly longer time to progression (P ⬍ .001) and better overall survival (P ⫽ .026). At 2 years, 12% of patients randomized to docetaxel were alive while all patients in the best supportive care group had died (the last death occurring at 20 months). Importantly, assignment to docetaxel also resulted in a clear improvement in clinical symptoms. The traditional schedule of docetaxel administration is 3-weekly. However, the drug is also active in NSCLC when given on a weekly basis. In a phase I study, the maximum tolerated dose was 43 mg/m2 per week given for 6 weeks, followed by
From the Department of Medicine, Medical University of South Carolina, Charleston. Dr Green has received honoraria and medical research grants from Aventis Pharmaceuticals Inc. Address reprint requests to Mark R. Green, MD, Medical University of South Carolina, 96 Jonathan Lucas St, 903 Clinical Sciences Building, Charleston, SC 29425. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2903-1204$35.00/0 doi:10.1053/sonc.2002.34259 17
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MARK R. GREEN
a 2-week rest.5 Myelosuppression was minimal, the dose limiting toxicities being fatigue and asthenia. In a subsequent phase II trial, the lower weekly dose of 36 mg/m2 docetaxel was given to 39 NSCLC patients who were aged 65 or over or had comorbidities.6 The overall response rate was 19%, with a further 36% of patients having stable disease. At 1 year, 28% of patients were alive. There were no cases of grade IV leukopenia or thrombocytopenia. It has recently been suggested that a schedule of weekly docetaxel for 3 weeks followed by an interval of 1 week may further improve tolerability in terms of asthenia, and that, at a weekly dose of 30 mg/m2, docetaxel produces essentially no alopecia. FIRST-LINE DOCETAXEL IN COMBINATION
McKay et al7 have investigated the combination of weekly docetaxel 30 mg/m2 plus weekly gemcitabine 800 mg/m2, with treatment given for 3 weeks followed by 1 week’s rest. Sixty-six elderly or “less fit” patients have been entered into the trial and 38 are currently evaluable. Among these patients, there have been one complete response and 10 partial responses (overall response rate, 29%), while a further 45% of patients had stable disease. A phase III trial of docetaxel alone versus docetaxel plus gemcitabine is planned in this patient group. Docetaxel can also be combined at relevant doses with platinum or vinorelbine. A phase II study of several docetaxel-based combinations has shown clear activity,8 and the Eastern Cooperative Oncology Group 1594 study, which randomized patients to one of four treatment arms, showed that 75 mg/m2 docetaxel plus 75 mg/m2 cisplatin was similar in activity to other regimens proposed for the first-line management of advanced NSCLC.9 The most recent data on docetaxel combinations in first-line therapy is further discussed below. Docetaxel Plus Cisplatin First-Line An article elsewhere in this supplement presents data from the recently completed TAX 326 study which involved a three-way randomization to regimens consisting of docetaxel plus cisplatin, docetaxel plus carboplatin, or a control arm of vinorelbine plus cisplatin.10 In this trial, patients assigned to 75 mg/m2 docetaxel plus cisplatin 75
mg/m2 every 3 weeks had significantly improved overall survival (P ⫽ .047) when compared with patients randomized to weekly vinorelbine 25 mg/m2 plus cisplatin 100 mg/m2 every 4 weeks. The two-year survival rate in the docetaxel/cisplatin arm was 21%, significantly greater than the 14% rate seen among patients assigned to vinorelbine plus cisplatin. Moreover, the combination of docetaxel/cisplatin was well tolerated, with dose intensity maintained close to 100%, and a low (4%) rate of febrile neutropenia. Docetaxel Plus Gemcitabine Docetaxel is also active first-line in combination with gemcitabine.8,11,12 In a now well-known study, Georgoulias et al8 randomized 371 patients with stage IIIB/IV disease and no prior chemotherapy to receive either docetaxel 100 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 2 or gemcitabine 1,100 mg/m2 on days 1 and 8 plus docetaxel on day 8.13,14 Lenograstim prophylaxis was included in both regimens. In this trial, in which a third of patients had IIIB disease and a third had adenocarcinomas, an excellent overall response rate was achieved using both regimens (Table 1). Intriguingly, there was an indication in these data that the docetaxel/gemcitabine combination might prove particularly active in patients with adenocarcinoma. The toxicity profile of both regimens was generally acceptable. Grade 4 anemia, mucositis, and neurotoxicity occurred with a frequency of 1% or less in the two arms of the trial. Grade 4 asthenia was experienced by 2% of patients of both treatment groups. However, as shown in Table 1, the docetaxel/gemcitabine combination had the advantage of causing significantly less grade 3/4 neutropenia, diarrhea, and nausea/vomiting. Docetaxel Plus Irinotecan The combination of docetaxel and irinotecan has also been evaluated in phase I and II studies as a first-line treatment of NSCLC. A Japanese group conducted a randomized phase II study comparing docetaxel 60 mg/m2 plus cisplatin 80 mg/m2 (both administered on day 1) against docetaxel 60 mg/m2 given on day 8 plus irinotecan 60 mg/m2 on days 1 and 8.15,16 Response and survival data showed no statistically significant differences between the two treatments (Table 2). The toxicity profiles of the two combinations, however, were
DOCETAXEL IN THE TREATMENT OF NSCLC
19
Table 1. Randomized Phase II Study of Docetaxel Plus Either Cisplatin or Gemcitabine: Efficacy and Safety13,14
Regimen Efficacy CR/PR ORR ORR by histology adenocarcinoma nonadenocarcinoma Median TTP Median survival 1-year survival Safety Neutropenia (grade 3/4) Febrile neutropenia Diarrhea (grade 3/4) Nausea/vomiting (grade 3/4)
Docetaxel ⫹ Cisplatin (N ⫽ 132)
Doctaxel ⫹ Gemcitabine (N ⫽ 114)
P Value
2%/30% 32%
1%/33% 34%
– –
20% 38% 8 mos 10 mos 42%
51% 23% 8 mos 9.5 mos 38%
.001 .02 – – –
33% 16%
22% 14%
.01 –
12%
3%
.002
10%
3%
.001
Abbreviations: CR, complete response; PR, partial response; ORR, overall response rate; TTP, time to progression.
clearly different; the docetaxel/cisplatin doublet causing more nausea/vomiting and the docetaxel/ irinotecan combination was associated with a higher incidence of diarrhea. Pectasides et al17 evaluated a triple combination regimen consisting of carboplatin (AUC of 2) plus docetaxel 20 mg/m2 plus irinotecan 60 mg/m2 given on days 1, 8, and 15 every 5 weeks together with prophylactic granulocyte-colony stimulating factor. Forty-seven previously untreated stage IIIB/IV patients were included, a response rate of 56% was observed, with a median survival of 14.8 months and a 1-year survival rate of 55%. Grade 3/4 neutropenia occurred in 26% of patients and 14% required antibiotics because of febrile neutropenia. Grade 3/4 nonhematologic toxicities included (% by patient): 28% diarrhea with 6% of patients requiring hospitalization; 18% nausea and vomiting; 10% neurotoxicity; and 10% fatigue. Even though the high activity observed with this triple combination was associated with a higher incidence of specific adverse events, the triplet combination was feasible and the response data justify further investigation.
DOCETAXEL IN STAGE III DISEASE AND EARLIER
As reviewed elsewhere in this supplement, the findings of the Southwest Oncology Group 9504 study, showing a median 26-month survival, twoyear survival of 51%, and three-year survival of 40% in patients treated with platinum/etoposide plus thoracic radiation followed by docetaxel, are undoubtedly provocative.18 One possibility is that these dramatically good results are because of the addition of docetaxel. Another possible explanation is that concurrent chemoradiation has become more effectively delivered with time. A third possibility is that the improvement is more apparent than real, and due to differences in patient selection and subtle stage migration, rather than any advance in treatment. The only way of resolving the question is to conduct a definitive, prospectively randomized trial in which patients receive platinum plus etoposide and thoracic radiotherapy followed either by three cycles of docetaxel or by two further cycles of platinum/etoposide. A second issue concerns the possible use of more aggressive docetaxel regimens in patients with stage III disease. Data suggest that weekly docetaxel is safe when given concurrently with thoracic radiation in patients with lung and esophageal cancer. This has been established by the study of Vokes et al,19 who administered 20 mg/m2 weekly docetaxel accompanied by radiation to 60 Gy, by the similar trial of Kourkourakis et al,20 who used 30 mg/m2 weekly docetaxel and twicedaily radiation to 64 Gy, and by Choy,21,22 who
Table 2. Randomized Phase II Study of Docetaxel Plus Either Cisplatin or Irinotecan15,16
Efficacy Overall response rate Progression free survival Median survival time 1-year survival Selected adverse events Neutropenia (grade 3/4) Nausea/vomiting (grade 2-4) Diarrhea (grade 2-4)
Docetaxel ⫹ Cisplatin (N ⫽ 51)
Docetaxel ⫹ Irinotecan (N ⫽ 57)
37% 146 days 49.5 wks 49%
32% 123 days 46.4 wks 41%
75% 86% 22%
83% 53% 44%
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MARK R. GREEN
administered 20 mg/m2 docetaxel plus carboplatin to an AUC of 2 and 60 Gy radiotherapy. Novel chemoradiation regimens based on upfront docetaxel suggest themselves. Might the combination of docetaxel plus cisplatin accompanied by radiation and followed by further cycles of docetaxel be more effective than platinum/etoposide chemoradiation followed by docetaxel? A further possibility would be to use an induction regimen of docetaxel plus cisplatin (or gemcitabine) to precede docetaxel/cisplatin chemoradiotherapy. Such thinking is underpinning a new generation of trials. In the phase III Southwest Oncology Group study, patients who have received platinum/etoposide plus thoracic radiation will be randomized to three courses of docetaxel with or without the addition of ZD1839. In a single-arm Southwest Oncology Group pilot study, patients will be treated with docetaxel plus cisplatin plus radiation, followed by docetaxel; and a Pancoast study will treat patients with platinum/etoposide chemoradiotherapy followed by docetaxel and then surgery. In addition, a European trial of induction chemotherapy will randomize stage IIIA N2/IIIB patients who have been treated with docetaxel plus cisplatin to either docetaxel plus concurrent radiation or thoracic radiotherapy alone. In patients with stage I to IIIA disease, induction regimens based on docetaxel alone or docetaxel in combination with cisplatin, carboplatin, or both cisplatin and gemcitabine have been investigated in phase II studies. Evidence to date suggests that surgery following such chemotherapy can be carried out without unexpected morbidity. Given the data of Georgoulias et al,13,14 the combination of docetaxel/gemcitabine is also a candidate for preoperative chemotherapy in patients with early stage NSCLC. However, the most exciting opportunities may lie in the combination of an active cytotoxic agent such as docetaxel with one or more novel agents based on molecular targeting. Drugs showing exciting promise include anti-angiogenesis agents, the signal transduction inhibitors (rTKI, FTI), antisense oligonucleotides targeting PKC or bcl-2, monoclonal antibodies such as trastuzumab, proteosome inhibitors (eg, PS341), and vaccines. DISCUSSION
Docetaxel is clearly highly active front-line and in the second-line therapy of patients with ad-
vanced or metastatic NSCLC. In both settings, randomized phase III data show a survival benefit in comparison with standard treatment. Docetaxel can be used three-weekly or weekly, and alone or in combination with other active agents. It has, in short, a major and growing contribution to make to the treatment of advanced and metastatic NSCLC. REFERENCES 1. Shepherd F, Dancey J, Ramlau R, et al: A prospective randomized trial of docetaxel (Taxotere) versus best supportive care in patients with non–small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18: 2095-2103, 2000 2. Fossella F, Devore R, Kerr R, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non–small cell lung cancer previously treated with a platinum containing agent. J Clin Oncol 18:2354-2363, 2000 3. Miller V, Kris M: Docetaxel (Taxotere) as a single agent and in combination chemotherapy for the treatment of patients with advanced non–small cell lung cancer. Semin Oncol 2:310, 2000 (suppl 3) 4. Roszkowski R, Pluzanska A, Krzakowski M, et al: A multicenter, randomized phase III study of docetaxel plus best supportive care in chemotherapy-naive patients with metastatic or non-resectable non–small cell lung cancer (NSCLC). Lung Cancer 27:145-157, 2000 5. Hainsworth JD, Burris HA, Erland JB, et al: Phase I trial of docetaxel administered by weekly infusion in patients with advanced refractory cancer. J Clin Oncol 16:2164-2168, 1998 6. Hainsworth JD, Burris HA, Litchy S, et al: Weekly docetaxel in the treatment of elderly patients with advanced non–small cell lung cancer: A Minnie Pearl Cancer Research Network phase II trial. Cancer 89:328-333, 2000 7. McKay CE, Hainsworth JD, Burris HA, et al: Weekly docetaxel/gemcitabine in the treatment of elderly patients (pts) with advanced non–small cell lung cancer (NSCLC): A Minnie pearl Cancer Research Network phase II trial. Proc Am Soc Clin Oncol 20:2793, 2001 (abstr) 8. Georgoulias V, Scagliotti G, Miller V, et al: Challenging the platinum combinations: Docetaxel (Taxotere) combined with gemcitabine or vinorelbine in non–small cell lung cancer. Semin Oncol 28:15-21, 2001 (suppl 2) 9. Schiller JH, Harrington D, Sandler A, et al: A randomized phase III trial of four chemotherapy regimens in advanced NSCLC. Proc Am Soc Clin Oncol 19:A-2, 2000 (abstr) 10. Rodriguez J, Pawel J, Pluzanska A, et al: A multicenter, randomized phase III study of docetaxel ⫹ cisplatin (DC) and docetaxel ⫹ carboplatin (DCb) vs. vinorelbine ⫹ cisplatin (VC) in chemotherapy-naive patients with advanced and metastatic non–small cell lung cancer. Proc Am Soc Clin Oncol 20:1252, 2001 (abstr) 11. Rizvi NA, Spiridonidis CH, Davis TH, et al: Docetaxel and gemcitabine combinations in non–small cell lung cancer. Semin Oncol 26:27-31, 1999 (suppl 16) 12. Hejna M, Kornek GV, Raderer M, et al: Treatment of patients with advanced nonsmall cell lung carcinoma using
DOCETAXEL IN THE TREATMENT OF NSCLC
docetaxel and gemcitabine plus granulocyte-colony stimulating factor. Cancer 89:516-522, 2000 13. Georgoulias V, Kourosis C, Androulakis N, et al: Frontline treatment of advanced non–small cell lung cancer with docetaxel and gemcitabine: A multicenter phase II trial. J Clin Oncol 17:914-920, 1999 14. Georgoulias V, Papadakis E, Alexopoulos A, et al: Platinum-based and non-platinum-based chemotherapy in advanced non–small-cell lung cancer: A randomised multicentre trial. Lancet 357:1478-1484, 2001 15. Takeda K, Yamamoto N, Negoro S, et al: Randomized phase II study of docetaxel (DOC) plus cisplatin (CDDP) versus DOC plus irinotecan in advanced non–small-cell lung cancer (NSCLC): A West Japan Thoracic Oncology Group (WJTOG) study. Proc Am Soc Clin Oncol 19:1944, 2000 (abstr) 16. Satouchi M, Takada Y, Takeda K, et al: Randomized phase II study of docetaxel (DOC) plus cisplatin (CDDP) versus DOC plus irinotecan in advanced non–small cell lung cancer (NSCLC): A West Japan Thoracic Oncology Group (WJTOG) study. Proc Am Soc Clin Oncol 20:1312, 2001 (abstr) 17. Pectasides D, Glotsos J, Bountouroglou N, et al: Weekly chemotherapy (CT) with carboplatin (CBDCA), docetaxel
21
(DOC) and irinotecan (CPT-11) in advanced non–small-cell lung cancer (NSCLC). A phase II study. Proc Am Soc Clin Oncol 20:2717, 2001 (abstr) 18. Gandara DR, Lovato LC, Albain KS, et al: Pathological stage IIIb non–small cell lung cancer (NSCLC): Prolonged survival with consolidation of docetaxel following concurrent chemoradiotherapy (SWOG 9504). Lung Cancer 29:92, 2000 (suppl 1) (abstr 302) 19. Vokes EE, Masters GA, Mauer AM, et al: Clinical studies of docetaxel (Taxotere) and concomitant chest therapy. Semin Oncol 24:S14-26 –S14-29, 1997 (suppl 14) 20. Koukourakis MI, Bahlitzanakis N, Froudarakis M, et al: Concurrent conventionally fractionated radiotherapy and weekly docetaxel in the treatment of stage IIIb non–small-cell lung carcinoma. Br J Cancer 80:1792-1796, 1999 21. Choy H: Combining taxanes with radiation for solid tumors. Int J Cancer 90:113-127, 2000 22. Choy H, DeVore RF, Porter LL, et al: Phase I trial of outpatients weekly docetaxel, carboplatin and concurrent thoracic radiation therapy for stage III unresectable non–small cell lung cancer. A Vanderbilt Cancer Center Affiliation Network (VCCAN) trial. Proc Am Soc Clin Oncol 18:475, 1999 (abstr 1833)
T
HIS ARTICLE reviews current knowledge about the treatment of non–small cell lung cancer (NSCLC) with docetaxel and assesses possibilities for further progress. DOCETAXEL IN SECOND-LINE THERAPY
Docetaxel is active in the treatment of patients with advanced NSCLC who have failed prior chemotherapy and is the only drug licensed in this setting. In a phase III trial, 75 mg/m2 docetaxel every 3 weeks was shown to improve survival when compared with best supportive care.1 Quality of life was enhanced and use of both palliative radiation and analgesic medication was reduced in the docetaxel group when compared with controls. Moreover, second-line docetaxel at 75 mg/m2 has been shown to improve 1-year survival when compared with an active control regimen of either vinorelbine or ifosfamide.2 Given this background, research interest in second-line therapy is now Seminars in Oncology, Vol 29, No 3, Suppl 12 (June), 2002: pp 17-21
focused on the use of docetaxel in combination with other cytotoxic agents or with novel cytostatics. FIRST-LINE ACTIVITY IN THREE-WEEKLY AND WEEKLY SCHEDULES
When used on an every-3-weeks schedule, docetaxel has substantial first-line activity in NSCLC.3 Pooling data from four phase II studies involving a total of 157 patients shows an overall response rate of 25%, a median survival of 9.9 months, and a 1-year survival rate (based on three studies) of 38%. Collectively, these data show a level of activity for docetaxel that is as high and as consistent as has been achieved with any other single agent in this setting. Furthermore, docetaxel has been proven superior to best supportive care alone in chemotherapy-naive patients with metastatic or non-resectable NSCLC.4 In this phase III trial by Roszkowski et al,4 207 patients were randomized to receive either 100 mg/m2 docetaxel every 3 weeks or best supportive care. Compared with the control arm, patients assigned to docetaxel had significantly longer time to progression (P ⬍ .001) and better overall survival (P ⫽ .026). At 2 years, 12% of patients randomized to docetaxel were alive while all patients in the best supportive care group had died (the last death occurring at 20 months). Importantly, assignment to docetaxel also resulted in a clear improvement in clinical symptoms. The traditional schedule of docetaxel administration is 3-weekly. However, the drug is also active in NSCLC when given on a weekly basis. In a phase I study, the maximum tolerated dose was 43 mg/m2 per week given for 6 weeks, followed by
From the Department of Medicine, Medical University of South Carolina, Charleston. Dr Green has received honoraria and medical research grants from Aventis Pharmaceuticals Inc. Address reprint requests to Mark R. Green, MD, Medical University of South Carolina, 96 Jonathan Lucas St, 903 Clinical Sciences Building, Charleston, SC 29425. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2903-1204$35.00/0 doi:10.1053/sonc.2002.34259 17
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MARK R. GREEN
a 2-week rest.5 Myelosuppression was minimal, the dose limiting toxicities being fatigue and asthenia. In a subsequent phase II trial, the lower weekly dose of 36 mg/m2 docetaxel was given to 39 NSCLC patients who were aged 65 or over or had comorbidities.6 The overall response rate was 19%, with a further 36% of patients having stable disease. At 1 year, 28% of patients were alive. There were no cases of grade IV leukopenia or thrombocytopenia. It has recently been suggested that a schedule of weekly docetaxel for 3 weeks followed by an interval of 1 week may further improve tolerability in terms of asthenia, and that, at a weekly dose of 30 mg/m2, docetaxel produces essentially no alopecia. FIRST-LINE DOCETAXEL IN COMBINATION
McKay et al7 have investigated the combination of weekly docetaxel 30 mg/m2 plus weekly gemcitabine 800 mg/m2, with treatment given for 3 weeks followed by 1 week’s rest. Sixty-six elderly or “less fit” patients have been entered into the trial and 38 are currently evaluable. Among these patients, there have been one complete response and 10 partial responses (overall response rate, 29%), while a further 45% of patients had stable disease. A phase III trial of docetaxel alone versus docetaxel plus gemcitabine is planned in this patient group. Docetaxel can also be combined at relevant doses with platinum or vinorelbine. A phase II study of several docetaxel-based combinations has shown clear activity,8 and the Eastern Cooperative Oncology Group 1594 study, which randomized patients to one of four treatment arms, showed that 75 mg/m2 docetaxel plus 75 mg/m2 cisplatin was similar in activity to other regimens proposed for the first-line management of advanced NSCLC.9 The most recent data on docetaxel combinations in first-line therapy is further discussed below. Docetaxel Plus Cisplatin First-Line An article elsewhere in this supplement presents data from the recently completed TAX 326 study which involved a three-way randomization to regimens consisting of docetaxel plus cisplatin, docetaxel plus carboplatin, or a control arm of vinorelbine plus cisplatin.10 In this trial, patients assigned to 75 mg/m2 docetaxel plus cisplatin 75
mg/m2 every 3 weeks had significantly improved overall survival (P ⫽ .047) when compared with patients randomized to weekly vinorelbine 25 mg/m2 plus cisplatin 100 mg/m2 every 4 weeks. The two-year survival rate in the docetaxel/cisplatin arm was 21%, significantly greater than the 14% rate seen among patients assigned to vinorelbine plus cisplatin. Moreover, the combination of docetaxel/cisplatin was well tolerated, with dose intensity maintained close to 100%, and a low (4%) rate of febrile neutropenia. Docetaxel Plus Gemcitabine Docetaxel is also active first-line in combination with gemcitabine.8,11,12 In a now well-known study, Georgoulias et al8 randomized 371 patients with stage IIIB/IV disease and no prior chemotherapy to receive either docetaxel 100 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 2 or gemcitabine 1,100 mg/m2 on days 1 and 8 plus docetaxel on day 8.13,14 Lenograstim prophylaxis was included in both regimens. In this trial, in which a third of patients had IIIB disease and a third had adenocarcinomas, an excellent overall response rate was achieved using both regimens (Table 1). Intriguingly, there was an indication in these data that the docetaxel/gemcitabine combination might prove particularly active in patients with adenocarcinoma. The toxicity profile of both regimens was generally acceptable. Grade 4 anemia, mucositis, and neurotoxicity occurred with a frequency of 1% or less in the two arms of the trial. Grade 4 asthenia was experienced by 2% of patients of both treatment groups. However, as shown in Table 1, the docetaxel/gemcitabine combination had the advantage of causing significantly less grade 3/4 neutropenia, diarrhea, and nausea/vomiting. Docetaxel Plus Irinotecan The combination of docetaxel and irinotecan has also been evaluated in phase I and II studies as a first-line treatment of NSCLC. A Japanese group conducted a randomized phase II study comparing docetaxel 60 mg/m2 plus cisplatin 80 mg/m2 (both administered on day 1) against docetaxel 60 mg/m2 given on day 8 plus irinotecan 60 mg/m2 on days 1 and 8.15,16 Response and survival data showed no statistically significant differences between the two treatments (Table 2). The toxicity profiles of the two combinations, however, were
DOCETAXEL IN THE TREATMENT OF NSCLC
19
Table 1. Randomized Phase II Study of Docetaxel Plus Either Cisplatin or Gemcitabine: Efficacy and Safety13,14
Regimen Efficacy CR/PR ORR ORR by histology adenocarcinoma nonadenocarcinoma Median TTP Median survival 1-year survival Safety Neutropenia (grade 3/4) Febrile neutropenia Diarrhea (grade 3/4) Nausea/vomiting (grade 3/4)
Docetaxel ⫹ Cisplatin (N ⫽ 132)
Doctaxel ⫹ Gemcitabine (N ⫽ 114)
P Value
2%/30% 32%
1%/33% 34%
– –
20% 38% 8 mos 10 mos 42%
51% 23% 8 mos 9.5 mos 38%
.001 .02 – – –
33% 16%
22% 14%
.01 –
12%
3%
.002
10%
3%
.001
Abbreviations: CR, complete response; PR, partial response; ORR, overall response rate; TTP, time to progression.
clearly different; the docetaxel/cisplatin doublet causing more nausea/vomiting and the docetaxel/ irinotecan combination was associated with a higher incidence of diarrhea. Pectasides et al17 evaluated a triple combination regimen consisting of carboplatin (AUC of 2) plus docetaxel 20 mg/m2 plus irinotecan 60 mg/m2 given on days 1, 8, and 15 every 5 weeks together with prophylactic granulocyte-colony stimulating factor. Forty-seven previously untreated stage IIIB/IV patients were included, a response rate of 56% was observed, with a median survival of 14.8 months and a 1-year survival rate of 55%. Grade 3/4 neutropenia occurred in 26% of patients and 14% required antibiotics because of febrile neutropenia. Grade 3/4 nonhematologic toxicities included (% by patient): 28% diarrhea with 6% of patients requiring hospitalization; 18% nausea and vomiting; 10% neurotoxicity; and 10% fatigue. Even though the high activity observed with this triple combination was associated with a higher incidence of specific adverse events, the triplet combination was feasible and the response data justify further investigation.
DOCETAXEL IN STAGE III DISEASE AND EARLIER
As reviewed elsewhere in this supplement, the findings of the Southwest Oncology Group 9504 study, showing a median 26-month survival, twoyear survival of 51%, and three-year survival of 40% in patients treated with platinum/etoposide plus thoracic radiation followed by docetaxel, are undoubtedly provocative.18 One possibility is that these dramatically good results are because of the addition of docetaxel. Another possible explanation is that concurrent chemoradiation has become more effectively delivered with time. A third possibility is that the improvement is more apparent than real, and due to differences in patient selection and subtle stage migration, rather than any advance in treatment. The only way of resolving the question is to conduct a definitive, prospectively randomized trial in which patients receive platinum plus etoposide and thoracic radiotherapy followed either by three cycles of docetaxel or by two further cycles of platinum/etoposide. A second issue concerns the possible use of more aggressive docetaxel regimens in patients with stage III disease. Data suggest that weekly docetaxel is safe when given concurrently with thoracic radiation in patients with lung and esophageal cancer. This has been established by the study of Vokes et al,19 who administered 20 mg/m2 weekly docetaxel accompanied by radiation to 60 Gy, by the similar trial of Kourkourakis et al,20 who used 30 mg/m2 weekly docetaxel and twicedaily radiation to 64 Gy, and by Choy,21,22 who
Table 2. Randomized Phase II Study of Docetaxel Plus Either Cisplatin or Irinotecan15,16
Efficacy Overall response rate Progression free survival Median survival time 1-year survival Selected adverse events Neutropenia (grade 3/4) Nausea/vomiting (grade 2-4) Diarrhea (grade 2-4)
Docetaxel ⫹ Cisplatin (N ⫽ 51)
Docetaxel ⫹ Irinotecan (N ⫽ 57)
37% 146 days 49.5 wks 49%
32% 123 days 46.4 wks 41%
75% 86% 22%
83% 53% 44%
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MARK R. GREEN
administered 20 mg/m2 docetaxel plus carboplatin to an AUC of 2 and 60 Gy radiotherapy. Novel chemoradiation regimens based on upfront docetaxel suggest themselves. Might the combination of docetaxel plus cisplatin accompanied by radiation and followed by further cycles of docetaxel be more effective than platinum/etoposide chemoradiation followed by docetaxel? A further possibility would be to use an induction regimen of docetaxel plus cisplatin (or gemcitabine) to precede docetaxel/cisplatin chemoradiotherapy. Such thinking is underpinning a new generation of trials. In the phase III Southwest Oncology Group study, patients who have received platinum/etoposide plus thoracic radiation will be randomized to three courses of docetaxel with or without the addition of ZD1839. In a single-arm Southwest Oncology Group pilot study, patients will be treated with docetaxel plus cisplatin plus radiation, followed by docetaxel; and a Pancoast study will treat patients with platinum/etoposide chemoradiotherapy followed by docetaxel and then surgery. In addition, a European trial of induction chemotherapy will randomize stage IIIA N2/IIIB patients who have been treated with docetaxel plus cisplatin to either docetaxel plus concurrent radiation or thoracic radiotherapy alone. In patients with stage I to IIIA disease, induction regimens based on docetaxel alone or docetaxel in combination with cisplatin, carboplatin, or both cisplatin and gemcitabine have been investigated in phase II studies. Evidence to date suggests that surgery following such chemotherapy can be carried out without unexpected morbidity. Given the data of Georgoulias et al,13,14 the combination of docetaxel/gemcitabine is also a candidate for preoperative chemotherapy in patients with early stage NSCLC. However, the most exciting opportunities may lie in the combination of an active cytotoxic agent such as docetaxel with one or more novel agents based on molecular targeting. Drugs showing exciting promise include anti-angiogenesis agents, the signal transduction inhibitors (rTKI, FTI), antisense oligonucleotides targeting PKC or bcl-2, monoclonal antibodies such as trastuzumab, proteosome inhibitors (eg, PS341), and vaccines. DISCUSSION
Docetaxel is clearly highly active front-line and in the second-line therapy of patients with ad-
vanced or metastatic NSCLC. In both settings, randomized phase III data show a survival benefit in comparison with standard treatment. Docetaxel can be used three-weekly or weekly, and alone or in combination with other active agents. It has, in short, a major and growing contribution to make to the treatment of advanced and metastatic NSCLC. REFERENCES 1. Shepherd F, Dancey J, Ramlau R, et al: A prospective randomized trial of docetaxel (Taxotere) versus best supportive care in patients with non–small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18: 2095-2103, 2000 2. Fossella F, Devore R, Kerr R, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non–small cell lung cancer previously treated with a platinum containing agent. J Clin Oncol 18:2354-2363, 2000 3. Miller V, Kris M: Docetaxel (Taxotere) as a single agent and in combination chemotherapy for the treatment of patients with advanced non–small cell lung cancer. Semin Oncol 2:310, 2000 (suppl 3) 4. Roszkowski R, Pluzanska A, Krzakowski M, et al: A multicenter, randomized phase III study of docetaxel plus best supportive care in chemotherapy-naive patients with metastatic or non-resectable non–small cell lung cancer (NSCLC). Lung Cancer 27:145-157, 2000 5. Hainsworth JD, Burris HA, Erland JB, et al: Phase I trial of docetaxel administered by weekly infusion in patients with advanced refractory cancer. J Clin Oncol 16:2164-2168, 1998 6. Hainsworth JD, Burris HA, Litchy S, et al: Weekly docetaxel in the treatment of elderly patients with advanced non–small cell lung cancer: A Minnie Pearl Cancer Research Network phase II trial. Cancer 89:328-333, 2000 7. McKay CE, Hainsworth JD, Burris HA, et al: Weekly docetaxel/gemcitabine in the treatment of elderly patients (pts) with advanced non–small cell lung cancer (NSCLC): A Minnie pearl Cancer Research Network phase II trial. Proc Am Soc Clin Oncol 20:2793, 2001 (abstr) 8. Georgoulias V, Scagliotti G, Miller V, et al: Challenging the platinum combinations: Docetaxel (Taxotere) combined with gemcitabine or vinorelbine in non–small cell lung cancer. Semin Oncol 28:15-21, 2001 (suppl 2) 9. Schiller JH, Harrington D, Sandler A, et al: A randomized phase III trial of four chemotherapy regimens in advanced NSCLC. Proc Am Soc Clin Oncol 19:A-2, 2000 (abstr) 10. Rodriguez J, Pawel J, Pluzanska A, et al: A multicenter, randomized phase III study of docetaxel ⫹ cisplatin (DC) and docetaxel ⫹ carboplatin (DCb) vs. vinorelbine ⫹ cisplatin (VC) in chemotherapy-naive patients with advanced and metastatic non–small cell lung cancer. Proc Am Soc Clin Oncol 20:1252, 2001 (abstr) 11. Rizvi NA, Spiridonidis CH, Davis TH, et al: Docetaxel and gemcitabine combinations in non–small cell lung cancer. Semin Oncol 26:27-31, 1999 (suppl 16) 12. Hejna M, Kornek GV, Raderer M, et al: Treatment of patients with advanced nonsmall cell lung carcinoma using
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docetaxel and gemcitabine plus granulocyte-colony stimulating factor. Cancer 89:516-522, 2000 13. Georgoulias V, Kourosis C, Androulakis N, et al: Frontline treatment of advanced non–small cell lung cancer with docetaxel and gemcitabine: A multicenter phase II trial. J Clin Oncol 17:914-920, 1999 14. Georgoulias V, Papadakis E, Alexopoulos A, et al: Platinum-based and non-platinum-based chemotherapy in advanced non–small-cell lung cancer: A randomised multicentre trial. Lancet 357:1478-1484, 2001 15. Takeda K, Yamamoto N, Negoro S, et al: Randomized phase II study of docetaxel (DOC) plus cisplatin (CDDP) versus DOC plus irinotecan in advanced non–small-cell lung cancer (NSCLC): A West Japan Thoracic Oncology Group (WJTOG) study. Proc Am Soc Clin Oncol 19:1944, 2000 (abstr) 16. Satouchi M, Takada Y, Takeda K, et al: Randomized phase II study of docetaxel (DOC) plus cisplatin (CDDP) versus DOC plus irinotecan in advanced non–small cell lung cancer (NSCLC): A West Japan Thoracic Oncology Group (WJTOG) study. Proc Am Soc Clin Oncol 20:1312, 2001 (abstr) 17. Pectasides D, Glotsos J, Bountouroglou N, et al: Weekly chemotherapy (CT) with carboplatin (CBDCA), docetaxel
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