Medscape

Site Map   Your Account   Support   About Us   Marketplace
Offerings:  Medscape.com   Charts   Mobile   Logician   CBSHealthwatch

NOTE: To view the article with Web enhancements, go to:
http://www.medscape.com/adis/CDI/2001/v21.n03/cdi2103.01.schu/cdi2103.01.schu-01.html.

Combination Chemotherapy with Docetaxel and Carboplatin for Advanced Non-Small Cell Lung Cancer

W. Schuette, Department of Internal Medicine II, City Hospital Martha-Maria, Halle, Germany; I. Bork, B. Wollschläger, Department of Internal Medicine II, Martin-Luther-Universität, Halle-Wittenberg, Germany S. Schädlich, Department of Internal Medicine II, City Hospital Martha-Maria, Halle, Germany

[Clin Drug Invest 21(3):161-168, 2001. © 2001 Adis International Limited]

Abstract

Background: Docetaxel has shown promising single-agent activity in non-small cell lung cancer (NSCLC) and its activity can be enhanced by the addition of platinum compounds. Several studies indicate that carboplatin may be as effective as cisplatin but with better tolerability.
Objective: Aphase II study was performed to investigate the safety and efficacy of combination chemotherapy with docetaxel and carboplatin in patients with advanced NSCLC.
Patients and Methods: 30 chemotherapy-naïve patients with stage IIIB and IV NSCLC were treated with docetaxel 90 mg/m2 over 1 hour, followed by carboplatin administered according to a target area under the curve of 5 mg/ml/min (Calvert's formula). Treatment was repeated every 3 weeks for 6 cycles.
Results: Myelosuppression was the predominant toxicity. Grade 3 or 4 granulocytopenia occurred in 77% of the patients. However, granulocyte colony-stimulating factor (G-CSF) was not utilised and neutropenic fever did not occur. Grade 3 or 4 nail disorder developed in 27% of the patients. Other nonhaematological toxicities, including fluid retention, were mild to moderate. The objective response rate was 30% (two complete and seven partial responses). The median time to progression was 24 weeks and median survival 57 weeks. One-year survival was 56%.
Conclusions: The combination of docetaxel and carboplatin appears to be well tolerated and active in patients with advanced NSCLC.

Introduction

Advanced non-small cell lung cancer (NSCLC) has a dismal prognosis, with a median survival of 4 to 5 months and a 1-year survival rate of less than 20% with palliative care alone.[1,2] During the 1980s, cisplatin and carboplatin were shown to modestly improve survival, although objective response rates remained low (20%).[3-5] Meta-analyses have shown that cisplatin-containing chemotherapy produces a small but significant improvement in survival, compared with best supportive care alone.[6,7]

Carboplatin is a cisplatin analogue that appears to have similar efficacy to cisplatin in NSCLC.[3] As carboplatin is more convenient to administer and less toxic than cisplatin, with a lower incidence of nausea and vomiting, and less severe nephro-, neuro- and ototoxicity,[3,8-10] it is increasingly being used in combination treatment regimens.

Docetaxel, a semisynthetic taxoid that promotes microtubule assembly and inhibits depolymerisation, leading to cell cycle arrest and cell death,[11] is also active in NSCLC.[12-18] Eight phase II trials of single-agent docetaxel involving a total of 318 patients with previously untreated stage III/IV NSCLC have reported response rates ranging from 21 to 38%.[12-18] The pooled intent-to-treat objective response rate was 29% (95% CI 27 to 31%), and the overall median survival was 11 months (range 7-14 months).[19] Recent studies have evaluated the role of this agent in combination with other standard therapies for NSCLC, such as cisplatin and carboplatin.[1,20]

In vitro studies have shown that cell lines that are resistant to cisplatin are not cross-resistant to docetaxel.[21,22] This is consistent with the observation that docetaxel is active in patients who have progressed with cisplatin-based regimens.[16,18,23] The addition of cisplatin to docetaxel appears to increase response rates in NSCLC, but there is no clear evidence of an improved survival.[19] In chemotherapy-naïve patients with advanced NSCLC, cisplatin plus docetaxel has produced response rates of 33 to 45% and median survival times ranging from 8.4 to 10.7 months.[24-26] The main dose-limiting toxicity is neutropenia.

The use of carboplatin plus docetaxel has attracted considerable interest, partly because of the potential for reduced toxicity and an increased therapeutic index.[9,27] The first phase I study of docetaxel plus carboplatin aimed to achieve an area under the plasma concentration-time curve (AUC) of carboplatin 6 mg/ml/min (using Calvert's formula), while the docetaxel dose was incrementally increased from 65 mg/m2 to 100 mg/m2.[28] The maximum tolerated dose of docetaxel was 90 mg/m2, without granulocyte colony-stimulating factor (G-CSF) support, and the dose-limiting toxicity of both drugs was neutropenia. A subsequent multi-centre phase II trial of docetaxel 80 mg/m2 plus carboplatin AUC 6 mg/ml/min in 33 patients with advanced NSCLC has reported encouraging preliminary data, with objective responses (including one complete response) in 27 evaluable patients.[29,30] Treatment was generally well tolerated, although neutropenia occurred in 48% of cycles, and febrile neutropenia in 7% of cycles.

Because of the potential advantages of carboplatin over cisplatin, we evaluated the combination of carboplatin with docetaxel in a phase II trial of patients with locally advanced or metastatic NSCLC. In view of the relatively high incidence of neutropenia in a phase II trial with carboplatin AUC 6 mg/ml/min,[29] the target carboplatin AUC was reduced to 5 mg/ml/min in this study, and combined with docetaxel 90 mg/m2.

Patients and Methods

Patient Selection

Male and female patients aged 18 to 75 years with histologically proven stage IIIB or IVNSCLC and no prior chemotherapy were eligible for the study. Patients who had previously received radiation therapy were eligible provided the index lesion was outside the radiation field. Other eligibility criteria included bi-dimensionally measurable disease by chest x-ray or computed tomography (CT); an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; a minimum life expectancy of 12 weeks; adequate bone marrow function (absolute neutrophil count >/=2,000/mm3, platelet count >/=100,000/mm3), adequate hepatic function (total bilirubin </=1.25 times the upper normal limit); and adequate renal function (serum creatinine </=1.15 times the upper normal limit).

Exclusion criteria included: the presence of brain metastasis; pre-existing WHO grade 2 sensorimotor neurotoxicity; pregnancy or breast-feeding; secondary malignancy; another concomitant or prior malignant disease, except for nonmelanomatous skin cancer or in situ cervical cancer; active infection or any other serious medical condition.

The study was conducted in accordance with the principles of the Declaration of Helsinki, and the study protocol was approved by the local ethics committee. The nature and purpose of the study were fully discussed with each patient, and written informed consent was obtained before enrolment.

Patient Evaluation

Before entry into the study, a complete medical history and physical examination was obtained from each patient. Current weight and height, weight loss in the past 6 months, and ECOG performance status were documented. Laboratory and radiological studies included a complete blood cell count with differential and platelet count; liver function tests; chest x-ray; CT of the chest, abdomen and brain; and a bone scan. Abronchial biopsy was performed to confirm the diagnosis of NSCLC. The complete blood cell count was repeated twice a week during the study. Serum electrolytes, blood urea nitrogen and creatinine were repeated weekly unless the patient's clinical status required more frequent evaluations. Liver function and creatinine clearance were assessed before each course of treatment, and radiological studies (chest x-ray; CT only in case of tumour remission) were repeated before every second treatment course (every 6 weeks).

Efficacy Analysis

Tumour response was assessed according to standard ECOG criteria.[31] Complete response (CR) was defined as the complete disappearance of all clinical, radiological and biochemical tumour signs. Partial response (PR) was defined as a reduction by at least 50% in the sum of the products of the two longest perpendicular diameters of all lesions. Disease progression was defined as an increase in the sum of the products of the two longest perpendicular diameters of any measurable lesion by at least 25%. No change (NC) was defined as a regression of bidimensional disease less than that required to meet criteria for PR and disease progression.

Safety Analysis

Safety was assessed according to the National Cancer Institute's Common Toxicity Criteria. At least one blood sample per treatment cycle was required for patients to be evaluable for laboratory measures of toxicity.

Treatment

All patients received a 3-day corticosteroid premedication schedule in each cycle, with oral dexamethasone 8mg given twice daily on the days preceding and following the administration of docetaxel, and dexamethasone 16mg given intravenously 30 minutes before the infusion of docetaxel. Single doses of ondansetron 0.45 mg/kg were also given routinely. Chemotherapy consisted of docetaxel 90 mg/m2 given as a 1-hour intra-venous infusion followed by a 15- to 60-minute infusion of carboplatin administered according to the Calvert formula[32] to a target AUC of 5 mg/ml/min. The creatinine clearance as calculated by the Cockcroft-Gault formula[33] was used as an estimate of glomerular filtration rate in the Calvert formula. Treatment was repeated every 3 weeks for a maximum of 6 cycles in responding patients and those with NC.

One dose reduction per patient was planned for severe haematological toxicities (grade 4 neutropenia), from 90 to 75mg/m2 for docetaxel and from AUC 5 mg/ml/min to 4 mg/ml/min for carboplatin. No individual re-escalation of doses was allowed. G-CSF support could be given at the discretion of the treating physician. Therapy was discontinued in patients with progressive disease or after the development or persistence of unacceptable toxicity despite dose reduction.

Study Design and Statistical Analysis

The trial was designed as a prospective, open, single-centre phase II study to assess the efficacy and safety of the combination of docetaxel plus carboplatin in advanced NSCLC. All patients enrolled in the study were monitored for treatment related toxicity, response, time to progression and survival. All patients receiving two or more cycles of chemotherapy were evaluable for response, and all patients receiving at least one cycle were evaluable for toxicity and survival. Time to progression was measured in weeks from the first day of treatment to first documentation of disease progression (or to death if the patient died without disease progression) in patients achieving a CR, PR or NC. Survival was measured in weeks from the first day of treatment. Actuarial survival curves were calculated by the Kaplan-Meier method.[34]

The study protocol included an early-stopping rule that called for premature conclusion of the study if no responses were observed among the first 14 evaluable patients. The response rate end-point determined the sample size. It was calculated that at least 30 assessable patients were required for the study to detectan increase in response rate from 25%, which can usually be expected with chemotherapy in patients with advanced NSCLC, to 50% or more with a type 1 error of 2% and a statistical power of 82%.

Results

Between January 1997 and February 1998, 30 eligible patients were enrolled (table I). Half of the population (53%) had squamous cell carcinoma, and three-quarters (77%) had metastatic disease.

The 30 patients in this study received a total of 142 cycles of docetaxel and carboplatin. The median number of courses per patient was six (range 2-6). No dose modification was necessary, i.e. all treatment courses were administered at full doses of both agents. G-CSF support was only required in one patient due to the occurrence of grade 4 neutropenia.

Efficacy

All patients enrolled in the study were evaluable for efficacy assessment. Minimum follow-up was 1 year. Two patients achieved a CR and seven patients a PR, for an overall objective response rate of 30% (95% CI, 14.7 to 49.4%). In addition, 14 patients (47%) achieved stable disease (95% CI, 28.3 to 65.7%). Responses occurred predominantly in lung and nodal disease. The median time to progression was 24 weeks (range 6-70+ weeks). Median survival was 57 weeks (fig. 1), and the 1-year survival rate was 56% (95% CI, 37.4 to 74.5%).

FIG1

Figure 1. Actuarial survival curve of all 30 eligible patients. Median survival is 57 weeks, with a 1-year survival of 56%.

Toxicity

Grade 3 or 4 granulocytopenia occurred in 35% of all 142 evaluable treatment cycles (grade 4 in 5.6%) and in 77% of the patients. However, neutropenic fever did not occur. Grade 3 or 4 thrombocytopenia was observed in only 1.4% of the cycles.

All patients developed alopecia. Fluid retention was generally mild and reached a maximum of grade 2 in five patients. No patient discontinued treatment due to fluid retention. The neurosensory toxicity of the chemotherapy regimen was also mild and did not exceed grade 2 (table II). A total of 11 patients reported grade 1 neurotoxicity, while four patients experienced grade 2 symptoms. Grade 1 to 2 arthralgia was reported in only one patient. Severe nail disorder was observed in 27% of patients.

Discussion

The results of the present study suggest that this combination of docetaxel and carboplatin is well tolerated and active in the treatment of stage IIIB and IV NSCLC. The response rate of 30% observed in this study is similar to that reported with other recently evaluated combination therapy, such as cisplatin/vinorelbine or cisplatin/paclitaxel.[35] However, the median overall survival of 13.1 months and the 1-year survival rate of 56% in our study are both superior to that with the cisplatin based combinations. Our findings compare favourably with the results of several phase II trials in which docetaxel was combined with cisplatin, where response rates varied from 21 to 52% and median survival from 8 to 11 months.[24,36-38] Although several groups have recently initiated trials of docetaxel plus carboplatin, survival data have not yet been reported.

The combinations of docetaxel and either cisplatin or carboplatin have not been directly compared, although the two platinum compounds have been evaluated in combination with paclitaxel. Preliminary results from the randomised Pan-European trial of paclitaxel (200 mg/m2 )plus either cisplatin (80 mg/m2) or carboplatin(AUC= 6 mg/ml/min), indicate that the efficacy of these regimens in NSCLC is equivalent.[39] There was no difference in overall response rate for the cisplatin/paclitaxel combination compared with carboplatin/cisplatin (28% versus 25%, respectively), or in time to progression (4.2 months versus 3.0 months, respectively). A significantly improved median survival was observed in the cisplatin arm (9.8 months versus 8.5 months, p < 0.05), although 1-year survival was equivalent in each arm (38% in the cisplatin arm, 33% in the carboplatin arm). The overall toxicity of these combinations was similar. As expected, there was more neutropenia in the carboplatin arm and more renal toxicity, nausea and vomiting in the cisplatin arm. The final results of this trial may help to resolve the question of whether cisplatin or carboplatin is the preferred platinum compound for the treatment of patients with advanced NSCLC.

In addition, an ongoing four-arm randomised trial has been designed by ECOG to compare docetaxel (75 mg/m2) plus cisplatin (75 mg/m2 )in the treatment of advanced NSCLC with the ECOG standard therapy of paclitaxel (135 mg/m2 )plus cisplatin (75 mg/m2 ) and with paclitaxel plus carboplatin, and gemcitabine plus cisplatin.[35] Its results will provide further insight into the comparative efficacy and tolerability of cisplatin and carboplatin used in combination with a taxoid in the treatment of advanced NSCLC.

Results from high-dose or dose escalation studies suggest that survival of patients with advanced NSCLC may be improved by the use of high dose-intensity chemotherapy. A Greek multicentre phase II trial that used high doses of docetaxel and cisplatin (100 mg/m2 and 80 mg/m2, respectively) with G-CSF support has demonstrated a 1-year survival rate of 48%.[24] Similarly, a study of paclitaxel plus carboplatin, conducted at the Fox Chase Cancer Center, used a high dose of carboplatin (AUC 7.5 mg/ml/min) and permitted individual dose escalation of paclitaxel by 40 mg/m2 per cycle to a maximum of 215 mg/m2, with routine administration of G-CSF. This approach produced a median survival of 12 months and a 1-year survival rate of 54%.[40] The results of the present study compare favourably with those from high-dose studies, despite the use of conventional doses of both docetaxel and carboplatin.

One benefit of our treatment combination was the good tolerability profile. Grade 4 granulocytopenia developed in only 5.6% of treatment cycles, there were no cases of neutropenic fever, and grade 3 or 4 thrombocytopenia was observed in only 1.4% of the cycles. Thrombocytopenia is considered to be the dose-limiting toxicity of single-agent carboplatin,[41] and this adverse effect appears to be mitigated by concomitant administration of paclitaxel.[42,43] The mechanism of this presumed platelet-sparing effect of paclitaxel is still unknown. Although the incidence of severe thrombocytopenia is generally reduced by pharmacokinetically-guided administration of carboplatin by target AUC, the results of the present study suggest that docetaxel may also protect platelets from carboplatin-induced damage. With the exception of severe nail disorders (27% of subjects), non-haematological toxicities were generally mild. Fluid retention was effectively controlled by routine premedication using a 3-day dexamethasone schedule.

The treatment-related toxicity in our study was lower than that reported with many other combination chemotherapy regimens used to treat NSCLC. A recent study of cisplatin plus vinorelbine reported an objective response rate of 26%, but 81% of patients experienced grade 3 or 4 neutropenia, and 10% developed neutropenic fever or sepsis.[35] As predicted, our combination of carboplatin/ docetaxel was also better tolerated than cisplatin/ docetaxel.[26] Treatment-related toxicity is an important consideration for patients with advanced cancer, given the trade-off between the modest survival benefit associated with chemotherapy and the impaired quality of life that may be associated with treatment. In addition, the low toxicity associated with the doses of carboplatin plus doxetacel used in this study provides an opportunity for further dose-escalation with haematopoietic growth factors in an attempt to increase response rates.

Conclusion

The present study demonstrates that the combination of docetaxel 90 mg/m2 and carboplatin AUC 5 mg/ml/min is active and well tolerated in advanced NSCLC. Although other treatment regimens have previously achieved similar response rates, the survival time with carboplatin plus docetaxel was one of the longest reported to date. Moreover, the good tolerability profile has clinical implications in terms of patient quality of life. Sub-sequent studies in which the doses of carboplatin and/or docetaxel are augmented may provide further progress in the treatment of advanced NSCLC.

Acknowledgements

This study was supported in part by a grant from Aventis (formerly Rhône-Poulenc Rorer), Germany GmbH.

Correspondence and offprints: Dr W. Schuette, Department of Internal Medicine II, City Hospital Martha-Maria, Röntgenstrasse 1, D-06120 Halle, Germany. E-mail: wolfgang.schuette@medizin.uni-halle.de

Table I. Baseline characteristics of patients with non-small cell lung cancer

CharacteristicNo.%
Eligible patients30100
Evaluable patients30100
Age (y)
   Median61.5 
   Range44-75 
Gender
   Male2790
   Female310
ECOG performance status
   0930
   12067
   213
Histology
   Adenocarcinoma517
   Squamous cell1653
   Large cell carcinoma310
   Undifferentiated620
Stage
   IIIB723
   IV2377
Prior radiation00
Metastatic sites (n = 23)
   Lung827
   Bone27
   Suprarenal517
   Liver1137
   Muscle13

Table II. Non-haematological toxicity

Toxicity% of patients (n = 30)
grade 1-2grade 3-4
Fatigue730
Nausea/vomiting630
Myalgia230
Arthralgia30
Stomatitis00
Diarrhoea230
Neuropathy500
Fluid retention560

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 1995; 311: 899-909
  2. Cullen MH, Billingham LJ, Woodroffe CM, et al. Mitomycin, ifosfamide and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 1999; 17: 3188-94
  3. Bunn Jr PA. Review of therapeutic trials of carboplatin in lung cancer. Semin Oncol 1989; 16: 27-33
  4. Bunn Jr PA. The expanding role of cisplatin in the treatment of non-small cell lung cancer. Semin Oncol 1989; 16: 10-21
  5. Ihde DC. Chemotherapy of lung cancer. N Engl J Med 1992; 327: 1434-41
  6. Soquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993; 342: 19-21
  7. Marino P, Pampallona S, Preatoni A, et al. Chemotherapy versus supportive care in advanced non-small cell lung cancer: results of a meta-analysis of the literature. Chest 1994; 106: 861-5
  8. Sørensen BT, Strömgren A, Jakobsen P, et al. Dose-toxicity relationship of carboplatin in combination with cyclophosphamide in ovarian cancer patients. Cancer Chemother Pharmacol 1991; 28: 39-401
  9. Bonomi PD, Finkelstein DM, Ruckdeschel JC, et al. Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small cell lung cancer. A study of the Eastern Cooperative Oncology Group. J Clin Oncol 1989; 7: 1603-13
  10. Kreisman H, Ginsberg S, Propert KJ, et al. Carboplatin or iproplarin in advanced non-small cell lung cancer: a Cancer and Leukemia Group B study. Cancer Treat Rep 1987; 71: 1049-52
  11. Ringel I, Horwitz SB. Studies with RP 56976 (Taxotere): a semi-synthetic analog of Taxol. J Natl Cancer Inst 1991; 83: 288-91
  12. Cerny T, Kaplan S, Pavlidis N, et al. Docetaxel (Taxotere) is active in non-small-cell lung cancer: a phase II trial of the EORTC Early Clinical Trials Group (ECTG). Br J Cancer 1994; 70: 384-7
  13. Francis PA, Rigas JR, Kris MG, et al. Phase II trial of docetaxel in patients with stage III and IV non-small-cell lung cancer. J Clin Oncol 1994; 12: 1232-7
  14. Miller VA, Rigas JR, Francis PA, et al. Phase II trial of a 75 mg/m2 dose of docetaxel with prednisone premedication for patients with advanced non-small cell lung cancer. Cancer 1995; 75: 968-72
  15. Fossella FV, Lee JS, Murphy WK, et al. Phase II study of docetaxel for recurrent or metastatic non-small-cell lung cancer. J Clin Oncol 1994; 12: 1238-44
  16. Burris H, Eckardt J, Fields S, et al. Phase II trials of Taxotere in patients with non small cell lung cancer [abstract no. 1116]. Proc Am Soc Clin Oncol 1993; 12: 335
  17. Watanabe K, Yokoyama A, Furuse K, et al. Phase II trial of docetaxel in previously untreated non-small cell lung cancer [abstract no. 1095]. Proc Am Soc Clin Oncol 1994; 13
  18. 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 1995; 13: 645-51
  19. Miller VA. Docetaxel in the management of advanced non-small cell lung cancer. Semin Oncol 1998; 25 Suppl. 8: 15-9
  20. Green MR, Kreisman H, Doll DC, et al. Carboplatin in non-small cell lung cancer: an update on the Cancer and Leukemia Group experience. Semin Oncol 1992; 19 Suppl. 2: 44-7
  21. Hill BT, Whelen RD, Shellard SA, et al. Differential cytotoxic effects of docetaxel in a range of mammalian tumour cell lines and certain drug resistant cell lines in vitro. Invest New Drugs 1994; 12: 169-82
  22. Kelland LR, Abel G. Comparative cytotoxicity of Taxol and Taxotere against cisplatin-sensitive and resistant human ovarian carcinoma cell lines. Cancer Chemother Pharmacol 1995; 30: 444-50
  23. Gandara DR, Voles E, Green M, et al. Activity of docetaxel in platinum-treated non-small-cell lung cancer: results of a phase II multicenter trial. J Clin Oncol 2000; 18: 131-5
  24. Georgoulias V, Androulakis N, Dimopoulos AM, et al. First-line treatment of advanced non-small-cell lung cancer with docetaxel and cisplatin: a multicenter phase II study. Ann Oncol 1998; 9: 331-4
  25. Le Chevalier T, Monnier A, Douillard JY, et al. Docetaxel (Taxotere) plus cisplatin: an active and well tolerated combination in patients with advanced non-small-cell lung cancer. Eur J Cancer 1998; 34: 2032-6
  26. Zalcberg J, Millward M, Bishop J, et al. Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer. J Clin Oncol 1998; 16: 1948-53
  27. Lee FH, Cabetta R, Usackk BF, et al. New platinum complexes in clinical trials. Cancer Treat Rev 1983; 10: 43-5
  28. Belani CP, Hadeed V, Ramanathan RK, et al. Docetaxel and carboplatin: a phase I and pharmacokinetic trial for advanced non-hematologic malignancies [abstract no. 771]. Proc Am Soc Clin Oncol 1997; 16: 220a
  29. Belani CP, Einzig A, Bonomi P, et al. Multi-institutional phase II trial of docetaxel and carboplatin combination in patients with stage IIIB and IV non-small cell lung cancer [abstract no. 52]. Lung Cancer 1997; 18: 16
  30. Capazzoli MJ, Belani CP, Einzig A, et al. Multi-institutional phase II trial of docetaxel and carboplatin combination in patients (pts) with stage IIIB and IV non-small cell lung cancer (NSCLC) [abstract no. 1845]. Proc Am Soc Clin Oncol 1998; 17: 479a
  31. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-55
  32. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7: 1748-56
  33. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41
  34. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81
  35. Sandler A. First-line combination chemotherapy for advanced non-small cell lung cancer: The Eastern Cooperative Oncology Group and Southwest Oncology Group Experience. Semin Oncol 1999; 26 Suppl. 15: 44-51
  36. Belani CP, Bonomi P, Dobbs T, et al. Multicenter phase II trial of docetaxel and cisplatin combination in patients with non-small cell lung cancer [abstract no. 1660]. Proc Am Soc Clin Oncol 1997; 16
  37. Faderl B, Pawel JV, Krauß C, et al. Phase 2 study of docetaxel (D) and cisplatin (CISPT) in a circadian timing as first line chemotherapy (CT) in advanced non small cell lung cancer (NSCLC) [abstract no. 1856]. Proc AmSoc Clin Oncol 1998; 17
  38. Cole JT, Gralla RJ, Rittenberg CN, et al. Defining the dose of docetaxel (Taxotere) in combination chemotherapy of non-small cell lung cancer: preserving efficacy with lower dose regimens [abstract no. 1671]. Proc Am Soc Clin Oncol 1997; 16
  39. Gatzemeier U, Rosell R, Belticher D, et al. Randomized Pan-European trial comparing paclitaxel/carboplatin versus paclitaxel/cisplatin in advanced non-small cell lung cancer [abstract no. 973]. Abstracts and Proceedings of ECCO 10. Sept 12-16, 1999; Vienna, Austria
  40. Langer CJ, Leighton JC, Comis RL, et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol 1995; 13: 1860-70
  41. McKeage MJ. Comparative adverse effect profiles of platinum drugs. Drug Safety 1995; 13: 228-44
  42. Siddiqui N, Boddy AV, Thomas HD, et al. A clinical and pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelial ovarian cancer. Br J Cancer 1997; 75: 287-94
  43. Vaughn D, Mick R, Ratajczak J, et al. Investigating the platelet sparing mechanism of paclitaxel/carboplatin chemotherapy [abstract no. 897]. Proc Am Soc Clin Oncol 1997; 16

HW-Clinical Trials

Site Map   Your Account   Support   About Us   Marketplace

Medscape Search Options
Select a database to search, enter a search term, then click “go.”    Advanced Search Forms

All material on this website is protected by copyright. Copyright © 1994-2001 by Medscape Inc. All rights reserved. This website also contains material copyrighted by 3rd parties. Medscape requires 3.x browsers or better from Netscape or Microsoft.