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Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non–Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy

From the University of Toronto, Toronto, and London Regional Cancer Centre, London, Ontario, Canada; Regional Hospital of Lung Disease and Tuberculosis, Poznan, Poland; Helsinki University, Helsinki, Finland; Alton Ochsner Medical Foundation, New Orleans, LA; Greenville Memorial Medical Center, Greenville, SC; University Hospitals of Cleveland, Cleveland, OH; Veterans Affairs Medical Center, Houston, TX; and Rhône-Poulenc Rorer, Collegeville, PA, and Paris, France.

Address correspondence to Frances A. Shepherd, MD, Princess Margaret Hospital, 610 University Ave, Ste 5-104, Toronto, Ontario M5G 2M9, Canada; email fshepherd{at}torhosp.toronto.on.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Investigators REFERENCES

 
PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non–small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life.

PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non–small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m² (49 patients) or 75 mg/m² (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks.

RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7.1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P < .001), as was median survival (7.0 v 4.6 months; log-rank test, P = .047). The difference was more significant for docetaxel 75 mg/m² patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P = .010; 1-year survival, 37% v 11%; ² test, P = .003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m², three of whom died, and in one patient treated with docetaxel 75 mg/m². Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups.

CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m², the benefits of docetaxel therapy outweigh the risks.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Investigators REFERENCES

 
THE RESULTS OF A large meta-analysis of 52 randomized clinical trials showed conclusively that the administration of chemotherapy offers a significant, but modest, survival advantage for all stages of non–small-cell lung cancer (NSCLC).¹ In early-stage disease, postoperative cisplatin-based adjuvant chemotherapy is associated with a hazards ratio of 0.87, which is equivalent to an absolute survival benefit of 5% at 5 years. For patients with more advanced tumors, the hazards ratio for chemotherapy is 0.73, with a 10% absolute improvement in survival at 1 year over supportive care alone. These results are all the more compelling because none of the studies in the meta-analysis used the newer and more active chemotherapy drugs that have become available in the last decade. Currently, randomized trials using the most active regimens for advanced NSCLC have shown consistent overall response rates of approximately 30% to 40% and 1-year survival rates of 35% to 40%.² This represents a clear advance over the 10% 1-year survival rate that can be expected with supportive care alone.

As chemotherapy gains wider acceptance for the treatment of earlier stages of NSCLC, particularly in the neoadjuvant setting, the practicing oncologist will be faced with a growing population of high performance status patients who have relapsed after their first-line chemotherapy. The role of second-line chemotherapy after initial treatment with a platinum-based regimen remains largely undefined. Most studies undertaken to date have been small phase II trials; drug dosages and schedules have varied considerably, and results have been reported incompletely.³ In a recent review of second-line chemotherapy for NSCLC, Fossella et al³ reported disappointing results for the treatment of this patient population. In almost half the studies, no responses were seen, and in most of the others, the overall response rate was less than 15%. Median and 1-year survival rates were seldom reported.

Docetaxel is one of the few agents that have been evaluated extensively in the second-line setting. Seven phase II trials of single-agent docetaxel in platinum-treated patients with NSCLC have been reported.^4-11 A total of 312 patients in these seven studies were treated with docetaxel 100 mg/m² every 3 weeks. Overall response rates ranged from 14% to 24%. Median survival was uniformly greater than 7 months, and, when reported, 1-year survival rates ranged from 25%⁶ to 44%.⁵

The promising results seen in these phase II studies of single-agent docetaxel led to the initiation of two large randomized trials of this agent for patients previously treated with cisplatin-based combination chemotherapy. We report here the results of one of these studies in which docetaxel treatment was compared with best supportive care (BSC).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Investigators REFERENCES

 
To be eligible for study, all patients must have received prior treatment with a platinum-containing (cisplatin or carboplatin) chemotherapy regimen. They may have received more than one chemotherapy regimen but could not have been treated previously with taxanes, including paclitaxel. All patients were required to have histologic or cytologic proof of unresectable locally advanced or metastatic NSCLC. Because response was only a secondary end point of this study, patients with both measurable and evaluable indicator lesions were eligible. Each patient was required to have a performance status of 2 or lower on the Eastern Cooperation Oncology Group (ECOG) scale, adequate hematologic parameters (WBC count 3.5 x 10⁹/L, absolute neutrophil count 2.0 x 10⁹/L, platelet count 100,000 x 10⁹/L), serum creatinine level of 2.0 mg/dL or lower, total bilirubin level less than or equal to the institutional upper limit of normal (ULN), and hepatic enzyme levels of 1.5 times the ULN or lower (with the exception of alkaline phosphatase, which could be up to five times the ULN). Patients were excluded if they had symptomatic or uncontrolled brain metastases or peripheral neuropathy greater than National Cancer Institute grade 2. Patients were still considered eligible if they had received prior radiation therapy, provided that 25% or less of their total bone marrow had been irradiated, but had to wait 30 days before entry onto the study. They were also required to wait 21 days before entry onto the study after being treated with any chemotherapy, immunotherapy, or biologic systemic anticancer therapy (42 days for mitomycin and nitrosoureas). All patients provided signed, written, informed consent.

Investigation and Treatment
Within 7 days of entry onto the study, all patients underwent a complete medical history and physical examination, including a full neurologic examination and documentation of ECOG performance status. Patients also underwent complete hematologic and biochemical testing and had an ECG and baseline chest x-ray performed. Within 3 weeks before the initiation of therapy, clinically indicated scans, including computed tomographic scans of the brain, thorax, and upper abdomen (or abdominal ultrasound) and radionuclide bone scans were performed.

All patients were required to complete quality-of-life (QOL) questionnaires before undergoing therapy. The Lung Cancer Symptom Scale was used in North America, and the European Organization for the Research and Treatment of Cancer quality-of-life questionnaire for lung cancer was used in Europe. Sixteen patients in North America and 25 patients in Europe completed both questionnaires.

Eligible patients were stratified on the basis of their ECOG performance status (0-1 v 2) and on their best response to prior platinum-based therapy (progression v no change, partial response, or complete response).

Patients randomized to the docetaxel arm were premedicated with oral dexamethasone 8 mg bid for 5 days (10 doses) starting 24 hours before each infusion of docetaxel. In the second half of the study, this regimen was reduced to a total of five doses. Docetaxel 100 mg/m² as a 1-hour intravenous infusion was administered every 21 days for the first half of the study. When interim safety-data monitoring identified a significantly higher toxic death rate in the chemotherapy arm of the study, the protocol was amended and the docetaxel dose was reduced to 75 mg/m² given intravenously over 1 hour every 3 weeks for the second half of the trial.

For patients who developed grade 4 neutropenia that lasted more than 7 days or that was associated with a temperature of more than 38°C, a 25% permanent dose reduction was required. Patients with grade 4 thrombocytopenia were re-treated with a 25% dose reduction after recovery. The dose was also reduced by 25% for grade 4 vomiting that could not be controlled by antiemetic drugs or for grade 3 or higher diarrhea. Treatment was discontinued in cases of grade 3 neuropathy.

Patients randomized to the BSC arm were treated with whichever therapy was judged to be appropriate by the treating physician. This treatment could have included treatment with antibiotics, analgesic drugs, transfusions, and palliative radiotherapy.

Patients in both arms of the study were evaluated every 3 weeks. At each follow-up visit, they underwent a complete medical history and physical examination, with documentation of weight and ECOG performance status. Vital signs were recorded and toxicities were evaluated. QOL questionnaires were also completed every 3 weeks. A chest x-ray was performed every 3 weeks, and scans were repeated every 6 weeks to document response or disease progression.

In the chemotherapy arm, treatment was continued until disease progression or unacceptable toxicity developed. In the BSC arm, patients continued to be evaluated as described above every 3 weeks for the first 18 weeks and then every 6 weeks.

Objective tumor response and duration of response were assessed only in the docetaxel arm. Standard World Health Organization response criteria were applied, and all responses had to be confirmed in 28 days or more after the initial documentation of response. Survival was calculated from the date of randomization until the date of death. Survival time was censored for loss of contact or initiation of antitumor therapy, including subsequent chemotherapy, immunotherapy, or surgery. Time to disease progression was assessed from the date of randomization until the date of disease progression. Time to disease progression was also censored at the last tumor assessment if there was no documentation of progression. Response duration was calculated from the date of randomization until the date of documentation of disease progression.

Statistical Considerations
The primary end point of the study was survival. The sample size was chosen on the basis of a log-rank test used to compare the two randomized groups. Comparisons of survival for the two halves of the study were made between the patients treated at docetaxel doses of either 100 mg/m² or 75 mg/m² and the corresponding BSC patients in that part of the trial. Secondary end points included objective tumor response and duration of response, as well as changes in QOL determined on the basis of the QOL instruments, changes in performance status and weight, and changes in analgesic use.

A sample size of 100 patients per group was estimated on the basis of a projected median survival of 7 months in the docetaxel group and 4 months in the BSC group and on the basis of the log-rank test with an alpha level of 5% (two-sided) and a power of 90% to compare the groups. The sample size was not estimated for an analysis intended to compare results within the four strata, as defined by performance status and response to prior therapy.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Investigators REFERENCES

 
The study opened in November 1994 and closed in December 1998. Thirty-six centers participated in the trial: 16 from the United States, 10 from Canada, three from Finland, two each from the United Kingdom and Poland, and one each from Hungary and Puerto Rico.

The baseline patient demographics are listed in Table 1. One hundred patients were randomized to the BSC arm and 104 to the docetaxel arm (49 at 100 mg/m², 55 at 75 mg/m²). One patient in each arm had an unconfirmed diagnosis of NSCLC. The two arms were well balanced with respect to sex, performance status, tumor stage, number of prior chemotherapy regimens, and best response to prior platinum-based chemotherapy.

View larger version (18K): [in this window] [in a new window]   Fig 1. A comparison of survival of all patients treated with docetaxel and all BSC patients.

View larger version (15K): [in this window] [in a new window]   Fig 2. A comparison of survival of (A) patients treated with docetaxel 100 mg/m2 and corresponding BSC patients and (B) patients treated with docetaxel 75 mg/m2 and corresponding BSC patients.

Toxicity
Six patients died within 30 days of receiving chemotherapy, five in the high-dose and one in the low-dose docetaxel arm, because of causes other than progressive disease. Three patients suffered fatal febrile neutropenia after treatment with docetaxel 100 mg/m². Two patients, one at each docetaxel level, developed pneumonia while they were not neutropenic. Whether a period of neutropenia before the onset of the pneumonia predisposed these patients to the development of infection remains speculative and unconfirmed. The sixth patient died at home of an unknown cause 8 days after treatment with docetaxel 100 mg/m².

The report of five possibly treatment-related deaths in the first 49 patients on the chemotherapy arm of the study led to a data and safety monitoring committee meeting to review the protocol and to make recommendations for change. Three deaths were clearly related to chemotherapy-induced neutropenia, and for the remaining two, a definite relationship to chemotherapy could not be established. Furthermore, no common prognostic factor, such as age or performance status, could be identified to account for this unusual number of toxic deaths. In view of these results, the protocol was amended to reduce the initial planned dose of docetaxel to 75 mg/m² for the remainder of the trial.

In the docetaxel arm, a total of 451 treatment cycles was administered. For the 49 patients treated at the 100-mg/m² dose, the median number of cycles was only two (range, 1 to 17), and only 68% of cycles could be delivered at the initial planned dose. The 55 patients treated with docetaxel 75 mg/m² received a median of four treatment cycles. At both doses, treatment could be delivered every 3 weeks in approximately 90% of cycles.

For the patients who received chemotherapy, hematologic toxicities are listed in Table 3. Grade 3 or 4 neutropenia occurred in 86% and 67% of patients treated with docetaxel 100 mg/m² and 75 mg/m², respectively. Eleven patients (22.4%) developed febrile neutropenia (three fatal cases) at the higher dose, compared with only one patient (1.8%) at the lower dose (no fatal cases). Grade 3 or 4 thrombocytopenia occurred in less than 1% of all chemotherapy cycles, and there were no episodes of clinical bleeding in either chemotherapy group. Grade 3 or 4 anemia occurred in 11 patients (10.6%): eight treated with docetaxel 100 mg/m² and three treated with 75 mg/m². Interestingly, 10.6% of the BSC patients reported grade 3 or 4 anemia as well.

As listed in Table 5, the use of all tumor-related medications was significantly less common in docetaxel-treated patients, compared with BSC patients (P = .02). Fewer docetaxel patients (32%) than BSC patients (49%) required morphine or morphine-equivalent medications for pain (P = .01). Nonmorphine analgesic use was also less frequent in docetaxel patients (39% v 55%; P = .03). Finally, 30% of docetaxel patients, compared with 49% of BSC patients, received medications for tumor-related indications other than pain (P < .01). Radiotherapy (at least one treatment during study treatment or follow-up) was required by fewer docetaxel patients (26% of docetaxel patients v 37% of BSC patients; P = .09).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Investigators REFERENCES

Variable and conflicting results have been reported in studies of second-line vinorelbine therapy. In two trials in which vinorelbine 25 mg/m²¹² or 20 mg/m²¹³ was administered weekly, no responses were seen. However, in a small 10-patient trial of vinorelbine 30 mg/m2 per week, a 20% response rate was reported by Sandoro et al.¹⁴

Numerous studies with paclitaxel also produced conflicting results, perhaps in part because of variability in both the dose and administration time of paclitaxel.³ No responses were seen in a small study in which paclitaxel 140 mg/m² was administered over 96 hours.¹⁵ In another trial in which paclitaxel 200 to 250 mg/m² was given over 24 hours, only two (14%) confirmed partial responses were observed, with two further responses that lasted less than 4 weeks.¹⁶ In two trials in which varying doses of paclitaxel were given over 1 hour, only one (2.5%) of 40 patients responded in one study,¹⁷ but there were 26 responses (23%) in the second.¹⁸

Gemcitabine has also demonstrated activity in the second-line setting. Rossi et al¹⁹ observed partial responses in six (20%) of 30 patients treated with gemcitabine 1,000 mg/m² weekly for 3 weeks. It is interesting that responses were also seen in two patients who had brain metastases and in two whose disease had progressed during cisplatin therapy.

Docetaxel has been studied more extensively than any other agent for the second-line treatment of NSCLC. In seven phase II trials, in which more than 300 patients were treated, response rates ranging from 14% to 24% were consistently reported.^3-11 In most of these studies, the docetaxel dose was 100 mg/m² intravenously over 1 hour every 3 weeks.

These promising phase II trial results led to two randomized studies of second-line docetaxel in patients previously treated with cisplatin-based chemotherapy. In one study (the TAX 320 trial), patients were randomized to receive docetaxel 100 mg/m², docetaxel 75 mg/m², or either vinorelbine 30 mg/m² weekly for 3 weeks given every 4 weeks or ifosfamide 2 g/m² daily for 3 days every 4 weeks, as chosen by each investigator.²⁰ In this study, patients could have received prior taxane therapy. Despite this, an advantage was demonstrated for treatment with docetaxel. Overall response rates of 11.9% and 7.5% were obtained for docetaxel at doses of 100 mg/m² and 75 mg/m², respectively, compared with only 1% for patients treated with either vinorelbine or ifosfamide. The best survival was seen in the docetaxel 75-mg/m² arm, in which 32% of patients were alive at 1 year, compared with 21% and 19% in the other two arms (² test P = .025).

The study reported here is the first to shed any light on the true role of second-line chemotherapy in the treatment of advanced NSCLC in that patients were randomized either to chemotherapy with docetaxel or to BSC. The overall response rate of 7% in our trial was less than that reported in any of the phase II studies of docetaxel but was similar to the results of the TAX 320 trial. This somewhat disappointing result may have been due to selection of a poorer group of patients with more advanced tumors. Approximately 80% of patients had stage IV disease; 25% were of ECOG performance status 2, and 25% had received two or more prior chemotherapy regimens. It is possible that only in this unfavorable population were investigators willing to run the risk of a 50% chance of no chemotherapy treatment.

Despite the low overall response rate, however, treatment with docetaxel was associated with significant prolongation of survival. Prolongation of median survival was seen with both doses of docetaxel, but the most marked improvement was associated with docetaxel 75 mg/m². The actual 1-year survival rate for patients treated at this dose was 37%. These results are similar to those obtained with first-line combination regimens.

In this study, the 100-mg/m² dose was associated with five reports of toxic deaths early in the trial. Three were thought to be related to docetaxel, and for the other two patients, an association with docetaxel treatment could not be ruled out. Excessive toxicity also contributed to diminished dose delivery. The median number of cycles delivered was only two, and this, combined with the 10% early death rate, may account for the lack of survival benefit seen at the 100-mg/m² dose. When the docetaxel dose was reduced to 75 mg/m² in the second half of the trial, dose delivery improved, with a median of four cycles given; the rate of febrile neutropenia fell from 22% to 2%, and there were no toxic deaths.

This high rate of toxic deaths was not seen in the 100 mg/m² arm of the TAX 320 study,¹⁶ nor in any of the other phase II studies, all of which used a 100-mg/m² dose. In the phase II trial from the M.D. Anderson Cancer Center, grade 4 neutropenia occurred in 85% of patients. This resulted in fever that required intravenous antibiotics in 16% of patients, but there was only one toxic death. In the multicenter trial reported by Gandara et al,⁶ the febrile neutropenia rate was similar, at 14%, but treatment-related death was not seen in 80 patients. Robinet et al⁸ also reported a 19% febrile neutropenia rate (11% by cycle) but no toxic deaths. We do not have a clear explanation as to why our patients experienced such a high toxic death rate at a dose of 100 mg/m². These patients were not elderly nor in a poor prognostic group, and this degree of toxicity could not have been predicted before treatment for any of them.

Salminen et al²¹ also reported a high degree of toxicity in heavily pretreated breast cancer patients who were given docetaxel 100 mg/m². Although none of their patients experienced a toxic death, almost half experienced treatment interruption because of toxicity. Salminen et al recommend a starting dose of 75 mg/m² in the second- and third-line treatment settings.

Nonhematologic toxicity was modest at both docetaxel doses. Grade 3 or 4 nausea and vomiting, diarrhea, and fluid retention were reported in less than 5% of patients and were never dose-limiting. It is of particular interest to note that the highest rates of neurosensory toxicity (3%) and asthenia (28%) occurred in patients on the BSC arm.

Clinical benefit in our study could be demonstrated by end points other than response and survival rates. A significant positive effect of docetaxel was evident in the analyses of both narcotic and nonnarcotic pain medication usage and in the need for radiation therapy. These observations are in keeping with those of Ellis et al,²² who showed that tumor-related symptoms could improve in as many as two thirds of patients, even though overall response rates may be as low as 25% to 30%.

In summary, this is the first trial to document that in good-performance patients with NSCLC, a trial of second-line chemotherapy is justified after first-line treatment with a platinum-based regimen. Treatment with docetaxel is associated with significant prolongation of survival and significant improvements in disease-related symptoms. At a dose of 75 mg/m², the benefits of docetaxel therapy outweigh the risks.

	APPENDIX Investigators

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Investigators REFERENCES

 
The following investigators contributed patients to this multicenter trial: Canada—Ronald Burkes, MD, Mount Sinai Hospital, Toronto, Ontario; Richard Gregg, MD, Kingston Regional Cancer Centre, Kingston, Ontario; Frances Shepherd, MD, Princess Margaret Hospital, Toronto, Ontario; Ronald Feld, MD, Princess Margaret Hospital, Toronto, Ontario; Vera Hirsch, MD, Montreal General Hospital, Montreal, Quebec; Jamie Skillings, MD, Nova Scotia Cancer Centre, Halifax, Nova Scotia; Karen Gelmon, MD, British Columbia Cancer Agency, Vancouver, British Columbia; Francis Laberge, MD, Hopital Laval, Sainte-Foy, Quebec; Shou-Ching Tang, MD, General Hospital, St. John’s, Newfoundland; Mark Vincent, MD, London Regional Cancer Centre, London, Ontario; Finland—Karin Mattson, MD, Helsinki University, Helsinki; Markku Pekonen, MD, Savonlinna Central Hospital, Savonlinna; Matti Salmo, MD, Vaasa Centre Hospital, Vaasa; Poland—Jacek Jassem, MD, Institute of Radiology, Gadansk; Rodryg Ramlau, MD, Regional Hospital of Lung Disease and Tuberculosis, Poznan; Hungary—Mel Kraszko, MD, Mellkasi Betegsegek Korhaza, Deszk; Puerto Rico— Luis Baez Diaz, MD, San Juan Municipal Hospital, San Juan; Sweden—Bent Bergman, MD, Avdelningen for Lungmedicim, Goteborg; United Kingdom—Robin Rudd, MD, St. Bartholomew Hospital, London, England; Allen Lamont, MD, Southend General Hospital, Essex, England; and United States—Howard Burris III, MD, Cancer Therapy and Research Center, San Antonio, TX; Alex Chang, MD, Genesee Hospital, Rochester, NY; Tracey Dobbs, MD, Baptist Regional Cancer Center, Knoxville, TN; Robert Figlin, MD, UCLA Medical Center, Los Angeles, CA; Richard Gralla, MD, Alton Ochsner Medical Foundation, New Orleans, LA; F. Anthony Greco, MD, Sarah Cannon Cancer Center, Nashville, TN; Laurent Gressot, MD, Veteran’s Affairs Medical Center, Houston, TX; Basil Kasimis, MD, VA New Jersey Healthcare, East Orange, NJ; Thomas Ladd, MD, University of Illinois at Chicago, Chicago, IL; Nathan Levitan, MD, University Hospitals of Cleveland, Cleveland, OH; Gershon Locker, MD, Evanston Hospital, Evanston, IL; Thomas Lynch, MD, Massachusetts General Hospital, Boston, MA; Vicki Morrison, MD, Veterans Affairs Medical Center, Minneapolis, MN; Mark O’Rourke, MD, Cancer Treatment Center, Greenville, SC; Lee Schwartzberg, MD, WestClinic, Memphis, TN; and Arnold Wax, MD, Las Vegas, NV.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Investigators REFERENCES

 
1. Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311:899-909, 1995[Abstract/Free Full Text]

2. Shepherd FA: Chemotherapy for non-small cell lung cancer: Have we reached a new plateau? Semin Oncol 26:3-11, 1999[Medline]

3. Fossella FV, Lee JS, Hong WK: Management strategies for recurrent non-small cell lung cancer. Semin Oncol 24:455-462, 1997[Medline]

4. Burris HA, Eckardt J, Fields S, et al: Phase II trials of Taxotere in patients with non–small-cell lung cancer. Proc Am Soc Clin Oncol 12:335a, 1993 (abstr 1116)

5. Fossella FV, Lee JS, Shin DM, et al: Phase II study of docetaxel for advanced or metastatic platinum-refractory non–small-cell lung cancer. J Clin Oncol 13:645-651, 1995[Abstract/Free Full Text]

6. Gandara DR, Vokes E, Green M, et al: Docetaxel (Taxotere^®) in platinum-treated non–small-cell lung cancer (NSCLC): Confirmation of prolonged survival in a multi-center trial. Proc Am Soc Clin Oncol 16:454a, 1997 (abstr 1632)

7. Robinet G, Kleisbaurer JP, Thomas P, et al: Phase II study of Taxotere (docetaxel) in advanced or metastatic non-small cell lung cancer previously treated with platinum. Ann Oncol 7:96-97, 1996 (suppl 5, abstr 458P)

8. Robinet G, Kleisbauer JP, Thomas P, et al: Phase II study of docetaxel (Taxotere) in first- and second-line NSCLC. Proc Am Soc Clin Oncol 16:480a, 1997 (abstr 1726)

9. Mattson K, Le Chevalier T, Stupp R, et al: Preliminary report of Phase II study of docetaxel (Taxotere^®) in locally advanced or metastatic non-small cell lung cancer. Ann Oncol 7:429a, 1996 (suppl 5, abstr)

10. Le Chevalier T: Docetaxel: Meeting the challenge of non-small cell lung cancer management. Anticancer Drugs 6:13-17, 1995 (suppl 4)

11. Yokoyama A, Kurita Y, Watanabe K: Early Phase II clinical study of RP56976 (docetaxel) in patients with primary pulmonary cancer: Docetaxel Cooperative Study Group for Lung Cancer. Gan To Kagaku Ryoho 21:2609-2616, 1994 (in Japanese)[Medline]

12. Pronzato P, Landucci M, Vaira F, et al: Failure of vinorelbine to produce responses in pretreated non-small cell lung cancer patients. Anticancer Res 14:1413-1416, 1994[Medline]

13. Rinaldi M, Della Giulia M, Venturo I, et al: Vinorelbine as single agent in the treatment of advanced non–small-cell lung cancer. Proc Am Soc Clin Oncol 13:360a, 1994 (abstr 1212)

14. Sandoro A, Maiorinol Sandoro M: Second-line treatment with vinorelbine in the weekly monotherapy chemotherapy for the treatment of advanced non-small cell lung cancer. Lung Cancer 11:130, 1994 (suppl 1, abstr 497)

15. Socinski MA, Steagall A: A phase II trial of 96-hour paclitaxel infusion in patients with non–small-cell lung cancer failing previous platinum-based or short-infusion paclitaxel therapy. Proc Am Soc Clin Oncol 16:482a, 1997 (abstr 1735)

16. Ruckdeschel J, Wagner H, Williams C, et al: Second-line chemotherapy for resistant metastatic non–small-cell lung cancer: The role of Taxol. Proc Am Soc Clin Oncol 13:357a, 1994 (abstr 1200)

17. Murphy WK, Winn RJ, Huber M, et al: Phase II study of taxol in patients with non-small cell lung cancer who have failed platinum-containing chemotherapy. Proc Am Soc Clin Oncol 13:363a, 1994 (abstr 1224)

18. Hainsworth JD, Thompson SD, Greco FA: Paclitaxel by 1-hour infusion: An active drug in metastatic non–small-cell lung cancer. J Clin Oncol 13:1609-1614, 1995[Abstract/Free Full Text]

19. Rossi A, Perrone F, Barletta R, et al: Activity of gemcitabine in cisplatin-pretreated patients with advanced non–small-cell lung cancer: A phase II trial. Proc Am Soc Clin Oncol 18:484a, 1999 (abstr 1868)

20. Fossella F, Devore R, Kerr R, et al: Randomized phase III study of Taxotere (T) (100 mg/m² and 75 mg/m²) versus vinorelbine (V) or ifosfamide (I) in non–small-cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy. Proc Am Soc Clin Oncol 17:483a, 1998 (abstr 1859)

21. Salminen E, Bergman M, Huhtala S, et al: Docetaxel: Standard recommended dose of 100 mg/m² is effective but not feasible for some metastatic breast cancer patients heavily pretreated with chemotherapy: A phase II single-center study. J Clin Oncol 17:1127-1131, 1999[Abstract/Free Full Text]

22. Ellis PA, Smith IE, Hardy JR, et al: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small cell lung cancer. Br J Cancer 71:366-370, 1995[Medline]

Submitted October 7, 1999; accepted January 25, 2000.

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				G. Giaccone, P. Zatloukal, J. Roubec, K. Floor, J. Musil, M. Kuta, R. J. van Klaveren, S. Chaudhary, A. Gunther, and S. Shamsili Multicenter Phase II Trial of YM155, a Small-Molecule Suppressor of Survivin, in Patients With Advanced, Refractory, Non-Small-Cell Lung Cancer J. Clin. Oncol., September 20, 2009; 27(27): 4481 - 4486. [Abstract] [Full Text] [PDF]

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