Paclitaxel and carboplatin in inoperable non-small-cell lung cancer: A phase II study

Annals of Oncology 8: 697-699, 1997. © 1997 Kluwer Academic Publishers. Printed in the Netherlands

Short report Paclitaxel and carboplatin in inoperable non-small-cell lung cancer: A phase II study P. A. Kosmidis,1 N. Mylonakis,1 G. Fountzilas,2 E. Samantas,3 A. Athanasiadis,2 E. Andreopoulou,4 N. Pavlidis4 & D. Skarlos3 l

The Hellenic Co-Operative Oncology Group and the Departments of Oncology at Meta.xa Cancer Hospital, Piraeus, 2Ahepa University Hospital, Thcssaloniki, ~Saint Anargiri Cancer Hospital, Kifisia, 4Ioannina University Hospital, Ioannina, Greece

ber of chemotherapy cycles was three, with a range of one to eight. Background: Based on the high activity of single-agent pacliResults: Of 55 evaluable patients, 15 (27.3%) achieved partaxel and the superior one-year survival rates of patients with tial responses, 15 (27.3%) had stable disease, and 25 (45.4%) non-small-cell lung cancer (NSCLC) treated with carboplatin, had progressive disease. The median survival was 8.95 months a phase II trial was initiated using both agents in patients with and 21.6% of the patients survived more than one year. Grade inoperable stages III and IV disease to investigate the efficacy 2/3 nonhematologic toxicity included alopecia (59%), neuroand toxicity of the combination. toxicity (3%), and myalgia/arthralgia (10%). Grade 2/3 neutroPatients and methods: Since July 1995, 60 patients fulfilling penia occurred in 14% of patients, whereas grade 3/4 thromboall eligibility criteria entered this study. All patients received cytopenia was seen in only 4%. One patient died of complicapaclitaxel 175 mg/m2 as a three-hour infusion, and carboplatin tions of a severe allergic reaction. dosed to an area under the concentration-time curve of Conclusion: Combination treatment using paclitaxel and seven, every three weeks. No granulocyte colony-stimulat- carboplatin is active and well tolerated in patients with inopering factor was given. Of the 56 male and four female patients, able non-small-cell lung cancer. The dose-response relationthe median age was 57 years (range 29 to 75 years) and the ship to paclitaxel and results of comparison with other platimedian Eastern Co-Operative Oncology Group performance num-based regimens remain to be determined. status was one. Most of the patients had stage IV (34) adenocarcinoma (31) with low differentiation (28). The median num- Key words: carboplatin, chemotherapy, NSCLC, paclitaxel Summary

Patients and methods

Combination chemotherapy has been reported to yield improved response rates with modest survival benefits in patients with advanced inoperable non-small-cell lung cancer (NSCLC) [1]. This gain often comes at the expense of substantial host toxicity, especially in patients without ideal performance status. In recent years several drugs with novel mechanisms of action and good activity against NSCLC have been identified. One promising new agent is paclitaxel which has demonstrated response rates of 21% to 24% and one-year survival rates of 30% to 40% [2]. In a five-arm study of cisplatin combinations and analogues, carboplatin has shown the best one-year survival rate with the least toxicity [3]. Based on the fact that both paclitaxel and carboplatin are active in NSCLC and can be administered in an outpatient setting, trials using a combination of these drugs are very attractive. The Hellenic Co-Operative Oncology Group undertook an investigation of the efficacy and toxicity of the paclitaxel and carboplatin combination in patients with NSCLC, and the results are reported here.

The primary objectives of this study were to investigate the response rate, survival rate, time to progression, and toxicity of the paclitaxel/ carboplatin combination in stage III/IV inoperable NSCLC patients without previous exposure to any chemotherapy regimens. Patients older than 18 years with histologically or cytologically documented stage IIIA inoperable, IIIB, or stage IV NSCLC (American Joint Committee in Cancer Staging Criteria) were eligible for this study, including those with recurrent disease following primary surgery or radiotherapy. Measurable or evaluable disease in a nonirradiated field was required unless subsequent progression was documented. Life expectancy exceeding 12 weeks and an Eastern Co-Operative Oncology Group performance status of less than two were further entrance requirements. Prior surgery or radiotherapy was allowed, but previous chemotherapy was not. Patients with brain metastasis were not eligible, nor were patients with active cardiac disease or those taking medications affecting cardiac performance. Women of childbearing age had to have a negative serum or urine pregnancy test within 48 hours of enrollment in the study. Initial laboratory requirements included a white blood cell count greater than 4,000/nl, platelet count greater than 100,000/uJ, bilirubin less than 1.2 mg/dl, normal alkaline phosphatase and gamma-GT, creatinine less than 1.4 mg/dl, and creatinine clearance greater than 70 ml/min. Finally, written informed consent was obtained. Patients were excluded from the study if they had past or current history of other neoplasms except for curativelytreated non-melanoma skin cancer, carcinoma in situ of the cervix, or

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Introduction

698 preexisting motor or sensory neurotoxicity grade = 2 according to World Health Organization criteria. Patients with an active infection and/or prior allergic reaction to drugs containing Cremophor were also excluded. After fulfilling eligibility criteria and undergoing staging procedures, all patients received the following chemotherapy dose schedule: paclitaxel, 175 mg/m 2 in a three-hour intravenous infusion, followed by carboplatin at a dose based on a targeted area under the concentration-time curve of seven according to the Calvert formula [4]. Treatment was repeated at three-week intervals. All patients received at least two cycles of combined treatment. At the conclusion of six cycles, patients - off therapy - were placed under observation, or if further improvement had been observed between the fourth and sixth cycles, treatment was continued at the discretion of the treating physician. Patients received hypersensitivity prophylaxis consisting of dexamethasone 20 mg 12 and 6 hours prior to paclitaxel infusion, and diphenhydramine 50 mg and cimetidine 300 mg 30 minutes before paclitaxel treatment.

No. of patients (%) Patients entered Male Female Median age (year) Range ECOG performance status* 0 1 2 Cigarette smokers Nonsmokers Weight loss > 10 kg Prior surgery Prior radiotherapy Primary Metastatic Stageb IIIA IIIB IV Histology Squamous cell Adenocarcinoma Large cell Mixed Undifferentiated Differentiation grade High Intermediate Low Nonspecified

60 56 (93.3) 4(6.7) 57 29-75 22 (36.7) 29 (48.3) 9(15.0) 53(88.3) 7(11.7) 12(20.0) 7(11.7) 5(8.3) 6(10.0) 6(10.0) 20 (33.3) 34 (56.7) 16(26.7) 31 (51.7) 4 (6.7) 1 (1.7) 8(13.2) 5 (8.3) 11(18.3) 28 (46.7) 16(26.7)

* ECOG = Eastern Co-Operative Oncology Group. b American Joint Committee in Cancer Staging Criteria.

Results Since July 1995, 60 patients fulfilling all eligibility criteria at four institutions have entered this study. The vast majority of patients were male with good performance status, stage IV adenocarcinoma of low differentiation. Their pretreatment characteristics are shown in Table 1. The median number of chemotherapy cycles was three (1-8). Only 15 cycles were delayed for one week. The median relative dose intensity for paclitaxel was 0.995. Fifty-five of 60 patients were finally evaluable for response, but none of them achieved complete response. Fifteen (27.3%) (95% CI: 15.3%-39.3%) patients responded partially, 15 (27.3%) (95% CI: 15.3%-39.3%) had stable disease, whereas 25 (45.4%) (95% CI: 32%58.9%) progressed. Most of the responses occurred in lung, lymph nodes and adrenals. Five patients were nonevaluable for the following reasons: Two discontinued treatment prior to the second cycle, one had a cerebral accident and a fourth died soon after initiation of chemotherapy due to rapid deterioration of his disease in the liver. The fifth patient developed a severe allergic reaction during the second cycle associated with bronchospasm, cyanosis, hypontention and confusion. The patient was intubated, the allergic reaction subsided following corticosteroids and adrenaline but he could not be extubated due to the severe chronic obstructive lung

disease. The patient ultimately succumbed to an upper respiratory tract infection. The median survival time was 8.95 months (0.2614.85), and the median time to progression 6.85 months (2-12.25). Thirteen (21.6%) patients have survived longer that one year. Toxicity: Hematologic toxicity was mild. Grade 3 anemia appeared in 3% of patients while grade 3 neutropenia occurred in 7%. Thrombocytopenia grades 3 and 4 was noted in 2% and 2%. Alopecia was the most prominent feature of nonhematologic toxicity. Nausea and vomiting were very mild. All patients had received ondansetron 24 mg i.v. prior to chemotherapy. Neurotoxicity, mainly numbness of finger tips, was mild and myalgia was moderate but lasted for two to four days following treatment (Table 2). No fever, infection, bleeding, or nephrotoxicity were noted.

Discussion During the past few years, a number of new chemotherapeutic drugs have been shown to be active against NSCLC, including paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan. Paclitaxel is particularly noteworthy, because in addition to the good response

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No dose reduction was permitted. In the event of hematologic toxicity but rather, treatment was delayed until the platelet count had risen above 100,000/ul, and the absolute granulocyte count above 1500/ ul. Patients were staged and response was assessed by clinical examination, chest X-rays and computerised tomography and, as indicated, abdominal computerised tomography, liver or adrenal ultrasound and bone scan. Disease parameters were measured at least every eight weeks; chest X-rays were repeated monthly. All histopathology slides were reviewed by the same group of pathologists. The usual criteria were followed for definition of response. Time to progression (TTP) was defined as the time elapsed from the start of treatment to renewed progression and survival from initiation of chemotherapy until death. Toxicity was evaluated according to the WHO grading system. Overall survival was estimated using the technique of Kaplan and Meier.

Table 1. Patient characteristics.

699 Table 2. Toxicity. Grade

1

Anemia Neutropenia Thrombocytopenia Nausea and vomiting AlopeciaNeurotoxicity Myalgia Allergic reaction

15(25%) 4(7%) 4 (7%) 6(10%) T(5%) 18(30%) 18(30%) 0 (0%)

6(10%) 2(3%) 4(7%) 4(7%) 0 (0%) 1 (2%) 3(5%) 1(2%) 21 (35%J " 13 (22%) 2(3%) 0(0%) 3(5%) 3(5%) 0 (0%) 0 (0%)

0(0%) 0(0%) 1 (2%) 0(0%) I (2%) 0(0%) 0(0%) 1 (2%)

Johnson et al. recently reported a similar response rate with a higher one-year survival rate [7]. In addition, higher response rates with the same combination of drugs have been reported by Langer et al. [8] as well as by Rowinski et al. [9]. The higher response rates observed in the latter two trials may well be related to the heterogeneity of the patients, but could also be related to differences in drug dose and dose intensity. Although the optimal dose of paclitaxel in NSCLC has not yet been defined recently published studies suggest the existence of a dose-response relationship [10].

References 1. Finkelstein DM, Ettinger DS, Ruckdeschel JC. Long-term survivors in metastatic non-small cell lung cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 1986; 4: 701-9. 2. Murphy WK, Fossella F.Winn RTet al. Phase II study of taxol in patients with untreated advanced non-small cell lung cancer. J. Natl Cancer Inst 1993; 85: 384-8. 3. Bonomi P, Finkelstein D, Ruckdeschel J 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: 1602-13. 4. Calvert AH, Newell DR, Gumbrell LA et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-55. 5. Kosmidis P, Mylonakis N, Skarlos D et al. A comparative study of cisplatin and vinblastine vs. ifosfamide, cisplatin, and vinblastine in non-operable non-small cell lung cancer. Ann Oncol 1994; 5: 159-62. 6. Rowinski EK, Donehower RC. Paclitaxel (Taxol). N. Engl J Med 1995; 332: 1004-14. 7. Johnson HD, Paul MD, Hande KR et al. Paclitaxel plus carboplatin in advanced non-small cell lung cancer: A phase II trial. J Clin Oncol 1996; 14: 2054-60. 8. Langer CJ, Leighton JC, Comis RL et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small cell lung cancer (NSCLC): A phase II toxicity, response and survival analysis (FCCC 93-624). J Clin Oncol 1995; 13: 1860-70. 9. Rowinski EK, Sartorins SE, Bowling MK et al. Paclitaxel on a three-hour schedule and carboplatin in non-small cell lung cancer. Use of maximally tolerated and clinically relevant single agent doses in combination is feasible. Proc Am Soc Clin Oncol 1995; 14: 354 (Abstr). 10. Hainsworth JD, Thompson DS, Greco FA et al. Paclitaxel by onehour infusion. An active drug in metastatic non-small cell lung cancer. J Clin Oncol 1995; 13: 1609-14. Received 12 February 1997; accepted 8 April 1997. Correspondence to: Paris Kosmidis, MD Head, Department of Medical Oncology Metaxa Cancer Hospital Botassi 51 Piraeus 18537 Greece

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rates it has been associated with high one-year survival rates in two different phase II studies [2]. In this phase II study, two active agents, paclitaxel and carboplatin, were combined to treat advanced NSCLC patients. This combination was found to be as active as other regimens that our group has used in the same disease in the past [5]. The response rate of 27.3% with a median survival time of 8.95 months and one-year survival rate of 21.6% are encouraging. In addition, the toxicities of this regimen were modest and for the most part, easily managed. The most common complication was grade 2 or 3 granulocytopenia. On the other hand, thrombocytopenia was very mild, less than anticipated from that of carboplatin alone. This fact potentiates the hypothesis of a favorable pharmacologic interaction between paclitaxel and carboplatin with respect to platelets. Nausea and vomiting were well controlled by ondansetron, but neurotoxicity, myalgia and arthralgia are still troublesome symptoms. Despite premedication, hypersensitivity reactions may occur and require careful observation. The only treatment-related death in this study was indirectly linked to hypersensitivity, analogous to another report in the literature [6].

In conclusion, the combination of paclitaxel and carboplatin is active against NSCLC with only limited toxic effects. Whether it is more active than other cisplatin-based regimens, however, remains to be seen.