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Vinorelbine and ifosfamide for unresectable non-small cell lung cancer
Lung Cancer 18 (1997) 95 – 100
Vinorelbine and ifosfamide for unresectable non-small cell lung cancer J.F. Morere *, S. Piperno-neumann, A. Brunet, C. Boaziz, M. Kohn, T. Bouillet, J.L. Breau Ser6ice d’Oncologie Me´dicale, CHU A6icenne, 125 route de Stalingrad, 93009, Bobigny, France Received 3 June 1996; received in revised form 9 April 1997; accepted 16 April 1997
Abstract Purpose: The study assessed the efficacy of combination therapy with vinorelbine and ifosfamide in patients with unresectable non-small cell lung cancer. Patients and methods: Forty patients with non-small cell lung cancer whose tumour was unresectable by virtue of the extent of disease or severity of impairment of lung function and who were considered unsuitable for treatment with a cisplatin based treatment were entered onto the study. Thirty-four patients received two cycles of treatment and were considered to be evaluable for response. The treatment schedule consisted of vinorelbine (Navelbine, Pierre Fabre Medicament) 25 mg/m2 on days 1 and 8, and ifosfamide 2 g/m2 per day with mesna 0.5 g/m2 three times daily given on days 1 to 3; cycles were repeated every 21 days and treatment continued in responding patients until progression occurred. Results: Objective responses were observed in 12 patients (30%; CI95, 16–44) with one complete response (CR) and 11 partial response (PR). Conclusion: This schedule achieves good levels of response without the use of cisplatin so it is suitable for patients whose performance status or concomitant medical condition precludes the use of platinum based chemotherapy. © 1997 Elsevier Science Ireland Ltd. Keywords: Chemotherapy; Ifosfamide; Non small cell lung cancer; Vinorelbine
* Corresponding author. Tel: + 33 1 48955131; fax: + 33 1 48955030. 0169-5002/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 1 6 9 - 5 0 0 2 ( 9 7 ) 0 0 0 4 4 - 5
96
J.F. Morere et al. / Lung Cancer 18 (1997) 95–100
1. Introduction The treatment of non-small cell lung cancer represents a major therapeutic challenge as most patients present with disease which is already inoperable or with metastatic spread [1]. Some benefit may still be obtained by chemotherapy for the majority of patients in whom surgery is not a therapeutic option, however only a limited number of cytotoxic drugs have demonstrable single agent activity capable of producing 15 – 20% responses [2]. Cisplatin, mitomycin C, ifosfamide and vindesine can all produce responses at the desired level of activity and when combination chemotherapy is examined, cisplatin based schedules clearly achieve the best results [3 – 5]. Vinorelbine, a new semisynthetic vinca-alkaloid has an activity which can achieve a 29% response rate as a single agent in the treatment of NSCLC. Combined with CDDP, Navelbine has demonstrated a statistically significant effect on survival. The toxicity associated with cisplatin is however substantial and the need for vigorous pre-hydration to avoid renal damage may preclude its use in a patient population with a high incidence of tobacco-related complicating medical conditions such as ischaemic heart disease [6]. It was therefore considered appropriate to combine ifosfamide and vinorelbine, two drugs with accepted single agent activity and attempt to define a schedule which achieved a high response rate and worthwhile palliation but avoided the poor tolerance associated with administration of cisplatin [7 – 13].
2. Patients and methods Patients entered in the study were required to have histologically proven nonsmall cell lung cancer which was unresectable (i.e. Stage IIIa with a poor pulmonary function, IIIb or IV). No prior therapy was permitted, and all patients were considered unsuitable for cisplatin based therapy by virtue of age, performance status (WHO PS ]2) or intercurrent medical conditions which prevented its safe administration. All patients were required to have bi-dimensionally measurable disease. Other eligibility criteria were as follows: expected survival ] 3 months; adequate bone marrow reserve (absolute granulocyte count ] 2000/l, platelet count ] 100 000/l and haemoglobin level ] 11 g/dl), adequate hepatic function including AST, ALT, bilirubin, alkaline phosphatase values B 1.25 times the upper limit of normal; there should be no evidence of peripheral neuropathy unless directly attributable to malignant disease. All patients who entered the study gave informed consent following the recommendations of the Helsinki Declaration and according to the French regulations. Treatment consisted of vinorelbine 25 mg/m2 on day 1 and 8 and ifosfamide 2 g/m2 per day with mesna 0.5 g/m2 three times daily on days 1–3. The first cycle was given in hospital with subsequent cycles administered in an outpatient setting if well tolerated. Antiemetic therapy consisted of ondansetron alone or in combination with methylprednisolone. Treatment cycles were repeated every 21 days; dose
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reductions of 20% applied to both agents were made if haematological toxicity greater than grade 3 was recorded. Treatment was continued in responding patients until progression occurred. Toxicity was evaluated according to WHO criteria on the basis of clinical and laboratory evaluation before each cycle and response was monitored after every two cycles by repeating appropriate clinical or radiological assessments of lesions with evaluation according to WHO grades. Forty patients were treated on study at the Hopital Avicenne, Bobigny, France between October 1992 and August 1995. All patients who received two cycles were considered to be assessable for response.
3. Results All forty patients were assessable for toxicity while 34 patients who received at least 2 cycles of therapy were assessable for response to treatment. The median age of the patient population was 65 years (range 49–74 years) and 45% of the patients had poor performance status (grade 2 or 3 at presentation). The other characteristics at presentation are summarised in Table 1. The reasons for which patients could not be included in the trial containing a CDDP regimen are described in Table 2. A total of 178 cycles were administered with patients receiving a median of 4 cycles (range 1 – 16). Of the 6 patients who only received one cycle, three had progressive disease, one required cryotherapy for serious haemoptysis, one discontinued treatment after an episode of bronchospasm and one patient died of congestive cardiac failure.
Table 1 Patient characteristics n
%
Performance status 0 1 2 3
3 19 16 2
Stage IIIA IIIB IV
4 18 18
Histology Squamous Adenocarcinoma Large cell Mixed
19 13 7 1
98
J.F. Morere et al. / Lung Cancer 18 (1997) 95–100
Table 2 Intercurrent medical conditions for CDDP excluded patients, n = 28
Creatinine elevation Hypoacusia Low limb polyneuritis Diabetes mellitus Systemic Hypertension Cardiac Insufficiency Cardio resporatory insufficiency Ischemic heart disease Disturbances of cardiac rythm
n
%
2 1 1 3 7 6 4 2 2
6 3 3 9 20 18 12 6 6
The treatment was well tolerated by most patients. Neutropenia was dose-limiting, affecting 32% of patients at grade 3 or 4. Non-haematological toxicity was mild with grade 1/2 alopecia affecting 13 patients (32%) and individual patients reporting mild rash, bronchospasm, myalgia all of which were reversible. Two patients suffered from Ifosfamide related encephalopathy which was reversible after methylene-blue infusion [20 – 25]. No patient experienced ifosfamide related haemorrhagic cystitis. The overall response rate was 30% (CI95 16–44%) with one CR and 11 PRs including 4 responses obtained in patients with stage IV disease (Table 3). Eleven of the patients with initial stage III disease received subsequent radiotherapy and 16 patients in the study proceeded to various forms of second-line chemotherapy. The median duration of response was 6 months (range 2–16) and median survival 10 months (range 1 – 36+). Three patients are still alive at 16, 30 and 48 months respectively. The median survival of responder patients is 21 months (range 10–48 months). The median survival for patients with stable disease is 11.5 months (range 1–19 months)
Table 3 Response rate according to patients characteristics CR
PR
Stage IIIA III B IV
— — 1
1 6 4
PS 0 1 2
— — 1
1 7 3
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4. Discussion The combination of vinorelbine and ifosfamide which has been evaluated in this study has achieved useful results in the management of patients with unresectable non-small cell lung cancer without recourse to cisplatin. The overall response rate of 30% was obtained in a patient population with relatively poor [5] performance status, extensive disease and a high incidence of intercurrent medical disorders and although the durability of the responses was not as good as that reported with more intensive three drug combinations [14–16], it was comparable to that achieved by other established approaches to treatment [5,11,12,17–19]. It is important to note that these results were achieved with very modest evidence of toxicity; neutropenia appeared to be transient and recovery was rapid, while other haematological and non-haematological toxicity was acceptable and easy manageable. This represents an excellent profile for a combination which is only ever destined to achieve improvements in a largely palliative setting, and certainly compares favourably with the problems of poor tolerance associated with any cisplatin based schedule [11]. It seems reasonable to conclude that the combination of vinorelbine and ifosfamide is a well-tolerated schedule in the management of patients with unresectable non-small cell lung cancer who are not suitable for treatment with cisplatin based schedules.
References [1] Minna JO, Higgins GA, Glatstein EJ. Cancer of the lung. In: De Vita VT, Hellman S, Rosenberg SA, editors. Cancer Principles and Practice of Oncology, Philadelphia – Toronto: J.B. Lippincott, 1982:396–474. [2] Cojean I, Le Chevalier T. Chemotherapy of stage IIIB and IV non-small cell lung cancer. Ann Oncol 1995;6:S41–4. [3] Souhami RL, Stewart LA, Arriagada R, et al. A data-based meta-analysis of randomised trials of chemotherapy versus best supportive care (BSC) in advanced non-small cell lung cancer (NSCLC). Lung Cancer 1994;11:24–5. [4] Souquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993;342:19– 21. [5] Thatcher N, Ranson M, Lee SM, Niven R, Anderson H. Chemotherapy in non-small cell lung cancer. Ann Oncol 1995;6:S83–95. [6] Carney DN, Byrne A. Treatment of the elderly small cell lung cancer patient. Lung Cancer 1994;11:230–1. [7] Ettinger DS. Ifosfamide in the treatment of non-small cell lung cancer. Sem Oncol 1989;16:31 – 8. [8] Depierre A, Lemarie E, Dabouis G, et al. Phase II study of navelbine (NVB) in non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 1988;7:778. [9] Depierre A, Lemarie E, Dabouis G, et al. A phase II study of navelbine (vinorelbine) in the treatment of non-small cell lung cancer. Am J Clin Oncol 1991;14:115 – 9. [10] Yokoyama A, Furuse K, Niitani H, et al. Multi-institutional phase II study of navelbine (vinorelbine) in non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 1992;11:957. [11] Le Chevalier T, Brisgand D, Douillard JY, et al. Randomized Study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: results of a european multicenter trial including 612 patients. J Clin Oncol 1994;12:360 – 7.
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[12] Depierre A, Chastang CI, Quoix E, et al. Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial. Ann Oncol 1994;5:37 – 42. [13] Berthaud P, Le Chevalier T, Ruffie P, et al. Phase I-II study of vinorelbine (navelbine) plus cisplatin in advanced non-small cell lung cancer. Eur J Cancer 1992;28A:1863 – 5. [14] Palackdharry CS, Krigel RL. Dose-intensive Ifosfamide/carboplatin/etoposide plus granylocytemacrophage colony stimulating factor for non-small cell lung cancer. Sem Oncol 1994;21:6 – 11. [15] Baldini E, Tibaldi C, Chella A, et al. Combination chemotherapy with vinorelbine, ifosfamide and cisplatin: a phase II study in stage IIIB-IV non-small cell lung cancer. Semin Oncol 1994;21:12 – 5. [16] Cullen MH, Mitomycin, ifosfamide and cisplatin in Non-small Cell Lung Cancer. Oncology 1993;50 Suppl.:31–34. [17] Vafai D, Israel V, Zaretski S, et al. Phase I/II trial of combination carboplatin and taxol in non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 1995;14:352. [18] Rowinsky EK, Sartorius SE, Bowling SE, et al. Paclitaxel as a 3-hour Schedule and carboplatin in non-small cell lung cancer: use of maximally tolerated and clinically relevant single agent doses in combination is feasible [abstract]. Proc Am Soc Clin Oncol 1995;14:354. [19] Lange CJ, Leighton J, Comis R, et al. Paclitaxel and carboplatin in advanced non-small cell lung cancer: toxicity, response and survival update [abstract]. Proc Am Soc Clin Oncol 1995;14:355. [20] Alonso JL, et al. Ifosfamide encephalopathy and methylene-blue: a case report. Ann Oncol 1996;7(6):643–5. [21] Harpey JP, Charpentier C, Coude M. Methylene-blue for riboflavin-unresponsive glutaricaciduria type II. The Lancet 1986;1(February 15):391. [22] Karnycheff F, et al. Bleu de methyle`ne. In: Husson MC, editor. Dossier du CNIMH-Revue d’Evaluation sur le Me´dicament. Paris: Centre National d’Information sur le Me´dicament Hospitalier, 1995:16–30. [23] Ku¨pfer A, et al. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet 1994;343(March 26):763–4. [24] Ku¨pfer C, Aeschlimann C, Cerny T. Methylene-blue and the neurotoxic mechanisms of ifosfamide encephalopathy. Europ J of Clin Pharmacol 1996;50(4):249 – 52. [25] Zulian GB, Tullen E, Maton B. Methylene-blue for ifosfamide associated encephalopathy. New Engl J Med 1995;332(18):1239–40.
.
Vinorelbine and ifosfamide for unresectable non-small cell lung cancer J.F. Morere *, S. Piperno-neumann, A. Brunet, C. Boaziz, M. Kohn, T. Bouillet, J.L. Breau Ser6ice d’Oncologie Me´dicale, CHU A6icenne, 125 route de Stalingrad, 93009, Bobigny, France Received 3 June 1996; received in revised form 9 April 1997; accepted 16 April 1997
Abstract Purpose: The study assessed the efficacy of combination therapy with vinorelbine and ifosfamide in patients with unresectable non-small cell lung cancer. Patients and methods: Forty patients with non-small cell lung cancer whose tumour was unresectable by virtue of the extent of disease or severity of impairment of lung function and who were considered unsuitable for treatment with a cisplatin based treatment were entered onto the study. Thirty-four patients received two cycles of treatment and were considered to be evaluable for response. The treatment schedule consisted of vinorelbine (Navelbine, Pierre Fabre Medicament) 25 mg/m2 on days 1 and 8, and ifosfamide 2 g/m2 per day with mesna 0.5 g/m2 three times daily given on days 1 to 3; cycles were repeated every 21 days and treatment continued in responding patients until progression occurred. Results: Objective responses were observed in 12 patients (30%; CI95, 16–44) with one complete response (CR) and 11 partial response (PR). Conclusion: This schedule achieves good levels of response without the use of cisplatin so it is suitable for patients whose performance status or concomitant medical condition precludes the use of platinum based chemotherapy. © 1997 Elsevier Science Ireland Ltd. Keywords: Chemotherapy; Ifosfamide; Non small cell lung cancer; Vinorelbine
* Corresponding author. Tel: + 33 1 48955131; fax: + 33 1 48955030. 0169-5002/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 1 6 9 - 5 0 0 2 ( 9 7 ) 0 0 0 4 4 - 5
96
J.F. Morere et al. / Lung Cancer 18 (1997) 95–100
1. Introduction The treatment of non-small cell lung cancer represents a major therapeutic challenge as most patients present with disease which is already inoperable or with metastatic spread [1]. Some benefit may still be obtained by chemotherapy for the majority of patients in whom surgery is not a therapeutic option, however only a limited number of cytotoxic drugs have demonstrable single agent activity capable of producing 15 – 20% responses [2]. Cisplatin, mitomycin C, ifosfamide and vindesine can all produce responses at the desired level of activity and when combination chemotherapy is examined, cisplatin based schedules clearly achieve the best results [3 – 5]. Vinorelbine, a new semisynthetic vinca-alkaloid has an activity which can achieve a 29% response rate as a single agent in the treatment of NSCLC. Combined with CDDP, Navelbine has demonstrated a statistically significant effect on survival. The toxicity associated with cisplatin is however substantial and the need for vigorous pre-hydration to avoid renal damage may preclude its use in a patient population with a high incidence of tobacco-related complicating medical conditions such as ischaemic heart disease [6]. It was therefore considered appropriate to combine ifosfamide and vinorelbine, two drugs with accepted single agent activity and attempt to define a schedule which achieved a high response rate and worthwhile palliation but avoided the poor tolerance associated with administration of cisplatin [7 – 13].
2. Patients and methods Patients entered in the study were required to have histologically proven nonsmall cell lung cancer which was unresectable (i.e. Stage IIIa with a poor pulmonary function, IIIb or IV). No prior therapy was permitted, and all patients were considered unsuitable for cisplatin based therapy by virtue of age, performance status (WHO PS ]2) or intercurrent medical conditions which prevented its safe administration. All patients were required to have bi-dimensionally measurable disease. Other eligibility criteria were as follows: expected survival ] 3 months; adequate bone marrow reserve (absolute granulocyte count ] 2000/l, platelet count ] 100 000/l and haemoglobin level ] 11 g/dl), adequate hepatic function including AST, ALT, bilirubin, alkaline phosphatase values B 1.25 times the upper limit of normal; there should be no evidence of peripheral neuropathy unless directly attributable to malignant disease. All patients who entered the study gave informed consent following the recommendations of the Helsinki Declaration and according to the French regulations. Treatment consisted of vinorelbine 25 mg/m2 on day 1 and 8 and ifosfamide 2 g/m2 per day with mesna 0.5 g/m2 three times daily on days 1–3. The first cycle was given in hospital with subsequent cycles administered in an outpatient setting if well tolerated. Antiemetic therapy consisted of ondansetron alone or in combination with methylprednisolone. Treatment cycles were repeated every 21 days; dose
J.F. Morere et al. / Lung Cancer 18 (1997) 95–100
97
reductions of 20% applied to both agents were made if haematological toxicity greater than grade 3 was recorded. Treatment was continued in responding patients until progression occurred. Toxicity was evaluated according to WHO criteria on the basis of clinical and laboratory evaluation before each cycle and response was monitored after every two cycles by repeating appropriate clinical or radiological assessments of lesions with evaluation according to WHO grades. Forty patients were treated on study at the Hopital Avicenne, Bobigny, France between October 1992 and August 1995. All patients who received two cycles were considered to be assessable for response.
3. Results All forty patients were assessable for toxicity while 34 patients who received at least 2 cycles of therapy were assessable for response to treatment. The median age of the patient population was 65 years (range 49–74 years) and 45% of the patients had poor performance status (grade 2 or 3 at presentation). The other characteristics at presentation are summarised in Table 1. The reasons for which patients could not be included in the trial containing a CDDP regimen are described in Table 2. A total of 178 cycles were administered with patients receiving a median of 4 cycles (range 1 – 16). Of the 6 patients who only received one cycle, three had progressive disease, one required cryotherapy for serious haemoptysis, one discontinued treatment after an episode of bronchospasm and one patient died of congestive cardiac failure.
Table 1 Patient characteristics n
%
Performance status 0 1 2 3
3 19 16 2
Stage IIIA IIIB IV
4 18 18
Histology Squamous Adenocarcinoma Large cell Mixed
19 13 7 1
98
J.F. Morere et al. / Lung Cancer 18 (1997) 95–100
Table 2 Intercurrent medical conditions for CDDP excluded patients, n = 28
Creatinine elevation Hypoacusia Low limb polyneuritis Diabetes mellitus Systemic Hypertension Cardiac Insufficiency Cardio resporatory insufficiency Ischemic heart disease Disturbances of cardiac rythm
n
%
2 1 1 3 7 6 4 2 2
6 3 3 9 20 18 12 6 6
The treatment was well tolerated by most patients. Neutropenia was dose-limiting, affecting 32% of patients at grade 3 or 4. Non-haematological toxicity was mild with grade 1/2 alopecia affecting 13 patients (32%) and individual patients reporting mild rash, bronchospasm, myalgia all of which were reversible. Two patients suffered from Ifosfamide related encephalopathy which was reversible after methylene-blue infusion [20 – 25]. No patient experienced ifosfamide related haemorrhagic cystitis. The overall response rate was 30% (CI95 16–44%) with one CR and 11 PRs including 4 responses obtained in patients with stage IV disease (Table 3). Eleven of the patients with initial stage III disease received subsequent radiotherapy and 16 patients in the study proceeded to various forms of second-line chemotherapy. The median duration of response was 6 months (range 2–16) and median survival 10 months (range 1 – 36+). Three patients are still alive at 16, 30 and 48 months respectively. The median survival of responder patients is 21 months (range 10–48 months). The median survival for patients with stable disease is 11.5 months (range 1–19 months)
Table 3 Response rate according to patients characteristics CR
PR
Stage IIIA III B IV
— — 1
1 6 4
PS 0 1 2
— — 1
1 7 3
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4. Discussion The combination of vinorelbine and ifosfamide which has been evaluated in this study has achieved useful results in the management of patients with unresectable non-small cell lung cancer without recourse to cisplatin. The overall response rate of 30% was obtained in a patient population with relatively poor [5] performance status, extensive disease and a high incidence of intercurrent medical disorders and although the durability of the responses was not as good as that reported with more intensive three drug combinations [14–16], it was comparable to that achieved by other established approaches to treatment [5,11,12,17–19]. It is important to note that these results were achieved with very modest evidence of toxicity; neutropenia appeared to be transient and recovery was rapid, while other haematological and non-haematological toxicity was acceptable and easy manageable. This represents an excellent profile for a combination which is only ever destined to achieve improvements in a largely palliative setting, and certainly compares favourably with the problems of poor tolerance associated with any cisplatin based schedule [11]. It seems reasonable to conclude that the combination of vinorelbine and ifosfamide is a well-tolerated schedule in the management of patients with unresectable non-small cell lung cancer who are not suitable for treatment with cisplatin based schedules.
References [1] Minna JO, Higgins GA, Glatstein EJ. Cancer of the lung. In: De Vita VT, Hellman S, Rosenberg SA, editors. Cancer Principles and Practice of Oncology, Philadelphia – Toronto: J.B. Lippincott, 1982:396–474. [2] Cojean I, Le Chevalier T. Chemotherapy of stage IIIB and IV non-small cell lung cancer. Ann Oncol 1995;6:S41–4. [3] Souhami RL, Stewart LA, Arriagada R, et al. A data-based meta-analysis of randomised trials of chemotherapy versus best supportive care (BSC) in advanced non-small cell lung cancer (NSCLC). Lung Cancer 1994;11:24–5. [4] Souquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993;342:19– 21. [5] Thatcher N, Ranson M, Lee SM, Niven R, Anderson H. Chemotherapy in non-small cell lung cancer. Ann Oncol 1995;6:S83–95. [6] Carney DN, Byrne A. Treatment of the elderly small cell lung cancer patient. Lung Cancer 1994;11:230–1. [7] Ettinger DS. Ifosfamide in the treatment of non-small cell lung cancer. Sem Oncol 1989;16:31 – 8. [8] Depierre A, Lemarie E, Dabouis G, et al. Phase II study of navelbine (NVB) in non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 1988;7:778. [9] Depierre A, Lemarie E, Dabouis G, et al. A phase II study of navelbine (vinorelbine) in the treatment of non-small cell lung cancer. Am J Clin Oncol 1991;14:115 – 9. [10] Yokoyama A, Furuse K, Niitani H, et al. Multi-institutional phase II study of navelbine (vinorelbine) in non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 1992;11:957. [11] Le Chevalier T, Brisgand D, Douillard JY, et al. Randomized Study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: results of a european multicenter trial including 612 patients. J Clin Oncol 1994;12:360 – 7.
100
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[12] Depierre A, Chastang CI, Quoix E, et al. Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial. Ann Oncol 1994;5:37 – 42. [13] Berthaud P, Le Chevalier T, Ruffie P, et al. Phase I-II study of vinorelbine (navelbine) plus cisplatin in advanced non-small cell lung cancer. Eur J Cancer 1992;28A:1863 – 5. [14] Palackdharry CS, Krigel RL. Dose-intensive Ifosfamide/carboplatin/etoposide plus granylocytemacrophage colony stimulating factor for non-small cell lung cancer. Sem Oncol 1994;21:6 – 11. [15] Baldini E, Tibaldi C, Chella A, et al. Combination chemotherapy with vinorelbine, ifosfamide and cisplatin: a phase II study in stage IIIB-IV non-small cell lung cancer. Semin Oncol 1994;21:12 – 5. [16] Cullen MH, Mitomycin, ifosfamide and cisplatin in Non-small Cell Lung Cancer. Oncology 1993;50 Suppl.:31–34. [17] Vafai D, Israel V, Zaretski S, et al. Phase I/II trial of combination carboplatin and taxol in non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol 1995;14:352. [18] Rowinsky EK, Sartorius SE, Bowling SE, et al. Paclitaxel as a 3-hour Schedule and carboplatin in non-small cell lung cancer: use of maximally tolerated and clinically relevant single agent doses in combination is feasible [abstract]. Proc Am Soc Clin Oncol 1995;14:354. [19] Lange CJ, Leighton J, Comis R, et al. Paclitaxel and carboplatin in advanced non-small cell lung cancer: toxicity, response and survival update [abstract]. Proc Am Soc Clin Oncol 1995;14:355. [20] Alonso JL, et al. Ifosfamide encephalopathy and methylene-blue: a case report. Ann Oncol 1996;7(6):643–5. [21] Harpey JP, Charpentier C, Coude M. Methylene-blue for riboflavin-unresponsive glutaricaciduria type II. The Lancet 1986;1(February 15):391. [22] Karnycheff F, et al. Bleu de methyle`ne. In: Husson MC, editor. Dossier du CNIMH-Revue d’Evaluation sur le Me´dicament. Paris: Centre National d’Information sur le Me´dicament Hospitalier, 1995:16–30. [23] Ku¨pfer A, et al. Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet 1994;343(March 26):763–4. [24] Ku¨pfer C, Aeschlimann C, Cerny T. Methylene-blue and the neurotoxic mechanisms of ifosfamide encephalopathy. Europ J of Clin Pharmacol 1996;50(4):249 – 52. [25] Zulian GB, Tullen E, Maton B. Methylene-blue for ifosfamide associated encephalopathy. New Engl J Med 1995;332(18):1239–40.
.