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cisplatin in advanced non-small-cell lung cancer (NSCLC)
Annals of Oncology 6: 833-835, 1995. O 1995 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Paclitaxel/cisplatin in advanced non-small-cell lung cancer (NSCLC) R. Pirker,1 G. Krajnik,1 S. Zochbauer,1 R. Malayeri,1 M. Kneussl2 & H. Huber1 'Department of Oncology, Clinic for Internal Medicine I; 2Department of Pulmology, Clinic for Internal Medicine IV; University of Vienna Medical School, Vienna, Austria
toxic effects. Partial responses were seen in 7 (35%) patients and no change in 9 (45%) patients. Major side effects inBackground: Paclitaxel (Taxol®) as single agent has shown cluded leukopenia, anemia, alopecia and dose-limiting promising activity in advanced non-small-cell lung cancer neurotoxicity. (NSCLC). Because paclitaxel lends itself to combination with Conclusions: Paclitaxel/cisplatin has shown good antiother anticancer drugs, we have determined the efficacy of tumor activity in patients with advanced NSCLC and should paclitaxel combined with cisplatin in patients with advanced be further evaluated in this disease. Because neurotoxicity NSCLC in a phase II trial. has been dose-limiting, methods for its prevention or early Patients and methods: Twenty patients with NSCLC stage detection should further enhance the clinical value of this INK or IV were treated with paclitaxel (175 mg/m2) as a combination chemotherapy. 3-hour infusion after standard premedication on day 1 and cisplatin (50 mg/m2 daily) on days 1 and 2. Treatment was repeated every 3 weeks. Key words: chemotherapy, cisplatin, neurotoxicity, nonResults: All 20 patients were evaluable for response and small-cell lung cancer, paclitaxel, phase II trial, Taxol" Summary
Introduction
Chemotherapy of locally advanced or metastatic nonsmall-cell lung cancer (NSCLC) is not only important for palliation of symptoms but, according to a recent meta-analysis, also results in prolongation of survival [1, 2]. New anticancer drugs which have shown promising efficacy in phase II trials should further improve the outcome of chemotherapy in patients with advanced NSCLC [3]. One of these drugs, paclitaxel (Taxol*), has recently been shown to have good activity as a single agent, with remission rates of 21% [4] and 24% [5], respectively. Neutropenia and anemia have been the major side effects. Because of its promising activity as a single agent and its low toxicity profile, paclitaxel lends itself to combination with other drugs active against NSCLC. The combination with cisplatin, a well established drug for the treatment of NSCLC, holds particularly great promise because both drugs have good efficacy as single agents [3], different mechanisms of action and different toxicity profiles except for peripheral neurotoxicity. Therefore, we have studied both the efficacy and toxicity of paclitaxel combined with cisplatin in patients with advanced NSCLC. Here we report the results of our trial.
by the ethical committee of the University of Vienna Medical School. Further inclusion criteria were measurable disease, age from 18 to 70 years, good performance status (Karnofsky >60), normal counts of leukocytes and thrombocytes, adequate renal (creatinine clearance >60 ml/min) as well as cardiac function and written informed consent. Patients with manifest cerebral metastasis were excluded. After standard premedication (20 mg dexamethasone given orally 12 hours and 6 hours before paclitaxel infusion, 50 mg diphenhydramine and 300 mg cimetidine given by intravenous injection 30 minutes prior to paclitaxel), patients received paclitaxel (175 mg/m2 by continuous infusion over 3 hours on day 1) followed by cisplatin (50 mg/m2 daily on days 1 and 2). In addition, standard antiemetics and sufficient pre- and post-hydration were administered. Treatment cycles were repeated every 3 weeks. Response was first evaluated after 2 cycles. Six further cycles were planned in instances of partial response and at least 1 more cycle in instances of no change. Progressive disease resulted in discontinuation of treatment. Objective response to treatment was determined radiologically by CT scan according to standard criteria [6]. Toxicity was evaluated according to WHO criteria.
Results
Twenty previously untreated patients (13 male, 7 female), aged 42-69 (median 61), with good performance statuses (13 Karnofsky 90%, 5 Karnofsky 80%, 2 Karnofsky 70%) were treated with paclitaxel/cisplatin. Eleven patients had adenocarcinomas, 4 had squamous cell carcinomas and 5 had undifferentiated large-cell carcinomas. Six (30%) patients had stage JBB Patients and methods disease and 14 (70%) had stage IV disease. Prior to inTwenty previously untreated patients with histologically proven clusion, 2 patients had undergone surgery and 7 had NSCLC stage TUB or IV were admitted to this trial after its approval received radiation therapy.
Downloaded from https://academic.oup.com/annonc/article-abstract/6/8/833/204426 by Queen Mary University of London user on 26 March 2018
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A total of 79 cycles (median 3.5, range 1-8) were administered. After 2 cycles, 5 patients had achieved partial responses. Two additional patients entered into partial response after 4 and 6 cycles. Thus, an overall partial response rate of 35% (95% confidence interval 15%-59%) was observed (Table 1A). With regard to tumor stage, 2/6 (33%) patients with stage 11IB and 5/14 (28%) with stage IV responded. Nine patients (45%) had no change and four patients (20%) progressed under chemotherapy (Table 1A). The period of overall response [6] ranged from 3 to 8+ months (median 6 months). Kaplan-Meier analysis [7] revealed a median overall survival of 10 months and a 1-year survival rate of 35%. The side effects of this combined treatment are summarized in Table IB. Major side effects included leukopenia (10% WHO grade 3-4) and anemia (5% WHO grade 3-4). Neutropenic fever occurred in 1 patient and resolved after antibiotic treatment and application of G-CSF. Leukopenia with a nadir usually around day 14 was of only short duration and did not result in any dose modification or delay of treatment. Neurotoxicity was seen in 70% of the patients including 5% WHO grade 3-4 (marked motor loss in both legs after 4 cycles in 1 patient who abused alcohol) and resulted in discontinuation of treatment in 7 patients after 3, 4, 5, 6 (3 patients) and 7 cycles. The patient in whom treatment was discontinued after only 3 cycles due to WHO grade 2 neurotoxicity suffered from an insulin-dependent diabetes mellitus with potentially preexisting but non-symptomatic neuropathy. Both the frequency and intensity of neurotoxicity increased with the numbers of treatment cycles. Discussion In this phase II trial, paclitaxel/cisplatin has shown good activity in patients with advanced NSCLC, with an overall response rate of 35%. Five patients achieved partial responses after only 2 cycles, and 2 achieved partial responses after 4 and 6 cycles, suggesting that prolonged treatment can be of clinical value. These results are consistent with the 34% partial response rate of a phase I/n trial that used paclitaxel doses of up to 225 mg/m2 and cisplatin doses of up to 120 mg/m2 [8]. Paclitaxel was infused over 3 hours prior to cisplatin because both this sequence of administration [9] and the 3-hour infusion duration (as compared to the 24hour infusion) [10] had been shown to be better tolerated. The paclitaxel dose of 175 mg/m2 in our study was slightly below the maximum dose (210 mg/m2) recommended for paclitaxel monotherapy administered as a 3-hour infusion without G-CSF [11]. In relapsed ovarian cancer patients, paclitaxel at 175 mg/m2 resulted in a significantly longer progression-free survival as compared to 135 mg/m2 [10].
Downloaded from https://academic.oup.com/annonc/article-abstract/6/8/833/204426 by Queen Mary University of London user on 26 March 2018
Table IA. Response data. Response
No. (%)
Partial response No change Progressive disease
7 (35) 9 (45) 4 (20)
Table IB. Toxicity.' WHO grade (%)
Leukopenia Anemia Thrombocytopenia Alopecia Nausea/vomiting Diarrhea Nephrotoxicity Allergic reaction Flush Neurotoxicity Syndrome characterized by myalgia, arthralgia, bone pain
0
1-2
3-4
55 35 85 5 40 70 80 40 30
35 60 15 95 60 30 20 60 65
10 5 5
35
65
-
1
Worst grade of toxicity experienced by each patient during treatment.
Hematoxicity was frequent but without clinical problems, as leukopenia usually resolved within a few days. However, neurotoxicity was both frequent and doselimiting and resulted in discontinuation of treatment in 7 patients. Whether neurotoxicity would be less pronounced with other dosages and/or schedules of administration remains to be seen. Nevertheless, the occurrence of neurotoxicity should be minimized by regular neurological monitoring including electrophysiological examinations that allow detection of subclinical neurotoxic effects and interruption of treatment at a stage at which severe clinical symptoms have not yet developed. Furthermore, patients with preexisting diseases often associated with neuropathy (e.g. diabetes mellitus, alcohol abuse) should be excluded from this treatment protocol. Because of its good efficacy, this combination holds promise not only for palliative treatment but also for both induction chemotherapy and adjuvant therapy in patients with NSCLC. In the latter 2 settings, the efficacy of this protocol is expected to be even higher because response to chemotherapy is usually better in early stages than in advanced disease [12]. In addition, because only 3-4 cycles of chemotherapy are usually administered for induction or adjuvant treatment, the cumulative drug doses required should be tolerable and without severe neurotoxicity. Finally, combinations of paclitaxel with other drugs, e.g., carboplatin, should be evaluated.
835
Acknowledgement This study was supported by Bristol-Myers Squibb. References 1. Souquet PJ, Chauvin F, Boissel JP et al. Polychemotherapy in advanced non-small-cell lung cancer A meta-analysis. Lancet 1993; 342:19-21. 2. GriUi R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer How much benefit is enough? J Clin Oncol 1993; 11: 1866-72. 3. Lilenbaum RC, Green MR. Novel chemotherapeutic agents in the treatment of non-small-cell lung cancer. J Clin Oncol 1993; 11:1391-402. 4. Chang AY, Kim K, Glick J et al. Phase II study of Taxol, Merbarone, and Piroxantrone in stage IV non-small-cell lung cancer. The Eastern Cooperative Oncology Group Results. J Natl Cancer Inst 1993; 85: 388-94. 5. Murphy WK, Fosella FV, Winn RJ et al. Phase II study of Taxol in patients with untreated advanced non-small-cell lung cancer. J Natl Cancer Inst 1993; 85: 384-8. 6. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. 7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81.
8. Belli L, Le Chevalier T, Gottfried M et al. Phase I—II trial of paclitaxel (Taxol) and cisplatin in previously untreated advanced non-small-cell lung cancer. Proc ASCO 1995; 14: 350. 9. Rowinsky EK, Gilbert M, McGuire WP et al. Sequences of taxol and cisplatin: A phase I and pharmacologic study. J Clin Oncol 1991; 9:1692-703. 10. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 1994; 12: 2654-66. 11. Schiller JH, Storer B, Tutsch K et al. Phase I trial of 3-hour infusion of paclitaxel with or without granulocyte colonystimulating factor in patients with advanced cancer. J Clin Oncol 1994; 2: 241-8. 12. Donnadieu N, Paesmans M, Sculier JP. Chemotherapy of nonsmall-cell lung cancer according to disease extent: A metaanalysis of the literature. Lung Cancer 1991; 7: 243-53. Received 16 June 1995; accepted 17 August 1995. Correspondence to: R. Pirker, MX). Department of Oncology Clinic for Internal Medicine I University of Vienna Medical School Wahringer Gurtel 18-20 A-1090 Vienna, Austria
Downloaded from https://academic.oup.com/annonc/article-abstract/6/8/833/204426 by Queen Mary University of London user on 26 March 2018
Short report Paclitaxel/cisplatin in advanced non-small-cell lung cancer (NSCLC) R. Pirker,1 G. Krajnik,1 S. Zochbauer,1 R. Malayeri,1 M. Kneussl2 & H. Huber1 'Department of Oncology, Clinic for Internal Medicine I; 2Department of Pulmology, Clinic for Internal Medicine IV; University of Vienna Medical School, Vienna, Austria
toxic effects. Partial responses were seen in 7 (35%) patients and no change in 9 (45%) patients. Major side effects inBackground: Paclitaxel (Taxol®) as single agent has shown cluded leukopenia, anemia, alopecia and dose-limiting promising activity in advanced non-small-cell lung cancer neurotoxicity. (NSCLC). Because paclitaxel lends itself to combination with Conclusions: Paclitaxel/cisplatin has shown good antiother anticancer drugs, we have determined the efficacy of tumor activity in patients with advanced NSCLC and should paclitaxel combined with cisplatin in patients with advanced be further evaluated in this disease. Because neurotoxicity NSCLC in a phase II trial. has been dose-limiting, methods for its prevention or early Patients and methods: Twenty patients with NSCLC stage detection should further enhance the clinical value of this INK or IV were treated with paclitaxel (175 mg/m2) as a combination chemotherapy. 3-hour infusion after standard premedication on day 1 and cisplatin (50 mg/m2 daily) on days 1 and 2. Treatment was repeated every 3 weeks. Key words: chemotherapy, cisplatin, neurotoxicity, nonResults: All 20 patients were evaluable for response and small-cell lung cancer, paclitaxel, phase II trial, Taxol" Summary
Introduction
Chemotherapy of locally advanced or metastatic nonsmall-cell lung cancer (NSCLC) is not only important for palliation of symptoms but, according to a recent meta-analysis, also results in prolongation of survival [1, 2]. New anticancer drugs which have shown promising efficacy in phase II trials should further improve the outcome of chemotherapy in patients with advanced NSCLC [3]. One of these drugs, paclitaxel (Taxol*), has recently been shown to have good activity as a single agent, with remission rates of 21% [4] and 24% [5], respectively. Neutropenia and anemia have been the major side effects. Because of its promising activity as a single agent and its low toxicity profile, paclitaxel lends itself to combination with other drugs active against NSCLC. The combination with cisplatin, a well established drug for the treatment of NSCLC, holds particularly great promise because both drugs have good efficacy as single agents [3], different mechanisms of action and different toxicity profiles except for peripheral neurotoxicity. Therefore, we have studied both the efficacy and toxicity of paclitaxel combined with cisplatin in patients with advanced NSCLC. Here we report the results of our trial.
by the ethical committee of the University of Vienna Medical School. Further inclusion criteria were measurable disease, age from 18 to 70 years, good performance status (Karnofsky >60), normal counts of leukocytes and thrombocytes, adequate renal (creatinine clearance >60 ml/min) as well as cardiac function and written informed consent. Patients with manifest cerebral metastasis were excluded. After standard premedication (20 mg dexamethasone given orally 12 hours and 6 hours before paclitaxel infusion, 50 mg diphenhydramine and 300 mg cimetidine given by intravenous injection 30 minutes prior to paclitaxel), patients received paclitaxel (175 mg/m2 by continuous infusion over 3 hours on day 1) followed by cisplatin (50 mg/m2 daily on days 1 and 2). In addition, standard antiemetics and sufficient pre- and post-hydration were administered. Treatment cycles were repeated every 3 weeks. Response was first evaluated after 2 cycles. Six further cycles were planned in instances of partial response and at least 1 more cycle in instances of no change. Progressive disease resulted in discontinuation of treatment. Objective response to treatment was determined radiologically by CT scan according to standard criteria [6]. Toxicity was evaluated according to WHO criteria.
Results
Twenty previously untreated patients (13 male, 7 female), aged 42-69 (median 61), with good performance statuses (13 Karnofsky 90%, 5 Karnofsky 80%, 2 Karnofsky 70%) were treated with paclitaxel/cisplatin. Eleven patients had adenocarcinomas, 4 had squamous cell carcinomas and 5 had undifferentiated large-cell carcinomas. Six (30%) patients had stage JBB Patients and methods disease and 14 (70%) had stage IV disease. Prior to inTwenty previously untreated patients with histologically proven clusion, 2 patients had undergone surgery and 7 had NSCLC stage TUB or IV were admitted to this trial after its approval received radiation therapy.
Downloaded from https://academic.oup.com/annonc/article-abstract/6/8/833/204426 by Queen Mary University of London user on 26 March 2018
834
A total of 79 cycles (median 3.5, range 1-8) were administered. After 2 cycles, 5 patients had achieved partial responses. Two additional patients entered into partial response after 4 and 6 cycles. Thus, an overall partial response rate of 35% (95% confidence interval 15%-59%) was observed (Table 1A). With regard to tumor stage, 2/6 (33%) patients with stage 11IB and 5/14 (28%) with stage IV responded. Nine patients (45%) had no change and four patients (20%) progressed under chemotherapy (Table 1A). The period of overall response [6] ranged from 3 to 8+ months (median 6 months). Kaplan-Meier analysis [7] revealed a median overall survival of 10 months and a 1-year survival rate of 35%. The side effects of this combined treatment are summarized in Table IB. Major side effects included leukopenia (10% WHO grade 3-4) and anemia (5% WHO grade 3-4). Neutropenic fever occurred in 1 patient and resolved after antibiotic treatment and application of G-CSF. Leukopenia with a nadir usually around day 14 was of only short duration and did not result in any dose modification or delay of treatment. Neurotoxicity was seen in 70% of the patients including 5% WHO grade 3-4 (marked motor loss in both legs after 4 cycles in 1 patient who abused alcohol) and resulted in discontinuation of treatment in 7 patients after 3, 4, 5, 6 (3 patients) and 7 cycles. The patient in whom treatment was discontinued after only 3 cycles due to WHO grade 2 neurotoxicity suffered from an insulin-dependent diabetes mellitus with potentially preexisting but non-symptomatic neuropathy. Both the frequency and intensity of neurotoxicity increased with the numbers of treatment cycles. Discussion In this phase II trial, paclitaxel/cisplatin has shown good activity in patients with advanced NSCLC, with an overall response rate of 35%. Five patients achieved partial responses after only 2 cycles, and 2 achieved partial responses after 4 and 6 cycles, suggesting that prolonged treatment can be of clinical value. These results are consistent with the 34% partial response rate of a phase I/n trial that used paclitaxel doses of up to 225 mg/m2 and cisplatin doses of up to 120 mg/m2 [8]. Paclitaxel was infused over 3 hours prior to cisplatin because both this sequence of administration [9] and the 3-hour infusion duration (as compared to the 24hour infusion) [10] had been shown to be better tolerated. The paclitaxel dose of 175 mg/m2 in our study was slightly below the maximum dose (210 mg/m2) recommended for paclitaxel monotherapy administered as a 3-hour infusion without G-CSF [11]. In relapsed ovarian cancer patients, paclitaxel at 175 mg/m2 resulted in a significantly longer progression-free survival as compared to 135 mg/m2 [10].
Downloaded from https://academic.oup.com/annonc/article-abstract/6/8/833/204426 by Queen Mary University of London user on 26 March 2018
Table IA. Response data. Response
No. (%)
Partial response No change Progressive disease
7 (35) 9 (45) 4 (20)
Table IB. Toxicity.' WHO grade (%)
Leukopenia Anemia Thrombocytopenia Alopecia Nausea/vomiting Diarrhea Nephrotoxicity Allergic reaction Flush Neurotoxicity Syndrome characterized by myalgia, arthralgia, bone pain
0
1-2
3-4
55 35 85 5 40 70 80 40 30
35 60 15 95 60 30 20 60 65
10 5 5
35
65
-
1
Worst grade of toxicity experienced by each patient during treatment.
Hematoxicity was frequent but without clinical problems, as leukopenia usually resolved within a few days. However, neurotoxicity was both frequent and doselimiting and resulted in discontinuation of treatment in 7 patients. Whether neurotoxicity would be less pronounced with other dosages and/or schedules of administration remains to be seen. Nevertheless, the occurrence of neurotoxicity should be minimized by regular neurological monitoring including electrophysiological examinations that allow detection of subclinical neurotoxic effects and interruption of treatment at a stage at which severe clinical symptoms have not yet developed. Furthermore, patients with preexisting diseases often associated with neuropathy (e.g. diabetes mellitus, alcohol abuse) should be excluded from this treatment protocol. Because of its good efficacy, this combination holds promise not only for palliative treatment but also for both induction chemotherapy and adjuvant therapy in patients with NSCLC. In the latter 2 settings, the efficacy of this protocol is expected to be even higher because response to chemotherapy is usually better in early stages than in advanced disease [12]. In addition, because only 3-4 cycles of chemotherapy are usually administered for induction or adjuvant treatment, the cumulative drug doses required should be tolerable and without severe neurotoxicity. Finally, combinations of paclitaxel with other drugs, e.g., carboplatin, should be evaluated.
835
Acknowledgement This study was supported by Bristol-Myers Squibb. References 1. Souquet PJ, Chauvin F, Boissel JP et al. Polychemotherapy in advanced non-small-cell lung cancer A meta-analysis. Lancet 1993; 342:19-21. 2. GriUi R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer How much benefit is enough? J Clin Oncol 1993; 11: 1866-72. 3. Lilenbaum RC, Green MR. Novel chemotherapeutic agents in the treatment of non-small-cell lung cancer. J Clin Oncol 1993; 11:1391-402. 4. Chang AY, Kim K, Glick J et al. Phase II study of Taxol, Merbarone, and Piroxantrone in stage IV non-small-cell lung cancer. The Eastern Cooperative Oncology Group Results. J Natl Cancer Inst 1993; 85: 388-94. 5. Murphy WK, Fosella FV, Winn RJ et al. Phase II study of Taxol in patients with untreated advanced non-small-cell lung cancer. J Natl Cancer Inst 1993; 85: 384-8. 6. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. 7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81.
8. Belli L, Le Chevalier T, Gottfried M et al. Phase I—II trial of paclitaxel (Taxol) and cisplatin in previously untreated advanced non-small-cell lung cancer. Proc ASCO 1995; 14: 350. 9. Rowinsky EK, Gilbert M, McGuire WP et al. Sequences of taxol and cisplatin: A phase I and pharmacologic study. J Clin Oncol 1991; 9:1692-703. 10. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 1994; 12: 2654-66. 11. Schiller JH, Storer B, Tutsch K et al. Phase I trial of 3-hour infusion of paclitaxel with or without granulocyte colonystimulating factor in patients with advanced cancer. J Clin Oncol 1994; 2: 241-8. 12. Donnadieu N, Paesmans M, Sculier JP. Chemotherapy of nonsmall-cell lung cancer according to disease extent: A metaanalysis of the literature. Lung Cancer 1991; 7: 243-53. Received 16 June 1995; accepted 17 August 1995. Correspondence to: R. Pirker, MX). Department of Oncology Clinic for Internal Medicine I University of Vienna Medical School Wahringer Gurtel 18-20 A-1090 Vienna, Austria
Downloaded from https://academic.oup.com/annonc/article-abstract/6/8/833/204426 by Queen Mary University of London user on 26 March 2018