A phase II study of oxaliplatin and paclitaxel in patients with advanced non-small-cell lung cancer

J. D. Winegarden1, A. M. Mauer1,*, G. A. Otterson2, C. M. Rudin1, M. A. Villalona-Calero2, V. J. Lanzotti2, L. Szeto1, K. Kasza1, P. C. Hoffman1 and E. E. Vokes1

1 University of Chicago Section of Hematology/Oncology and University of Chicago Cancer Research Center, Chicago, IL; 2 The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

Received 19 May 2003; revised 19 December 2003; accepted 29 January 2004


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Purpose:

To evaluate the efficacy and toxicity of oxaliplatin and paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC).

Patients and methods:

The treatment regimen was given as defined in a phase I investigation in patients with previously treated ovarian cancer. It consisted of paclitaxel 175 mg/m2 (1-h infusion) and oxaliplatin 130 mg/m2 (2-h infusion) given every 21 days. Eligible patients had stage IIIB (pleural effusion)/IV NSCLC, measurable disease, no prior chemotherapy, Eastern Cooperative Oncology Group performance status 0–2, and adequate hematological, renal and hepatic function.

Results:

A total of 38 patients were enrolled with the following characteristics: 29% male (n = 11); 71% female (n = 27); median age 64.5 years (range 37–78); performance status of 0–1 84% (n = 32); stage IIIB 8% (n = 3); stage IV 92% (n = 35). One hundred and eighty-one cycles were administered, with a median of four per patient (range one to 12). The overall objective response rate for all 38 patients was 34.2% [95% confidence interval (CI) 19.6% to 51.4%]. This response rate includes 13 patients who met criteria for a partial response. No complete responses were observed. Median overall survival time was 9.2 months (95% CI 6–12.4) and median progression-free survival time was 4.3 months (95% CI 2.1–6.5). The 1- and 2-year overall survival rates were 37% and 21%, respectively. Hematological toxicity included six patients with grade 4 neutropenia. Non-hematological toxicity consisted mainly of grades 1 and 2 neurosensory toxicity. Laryngodysesthesia was observed in two patients following oxaliplatin infusion. No grade 4 non-hematological toxicities were encountered.

Conclusion:

This regimen is well tolerated, and demonstrates activity in patients with advanced NSCLC.

Key words: non-small-cell lung cancer, oxaliplatin, paclitaxel


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Lung cancer is a leading cause of cancer-related mortality worldwide [1]. Most patients with non-small-cell lung cancer (NSCLC) typically present with stage IIIB–IV disease, leaving palliative chemotherapy as the major treatment option [2]. The benefits of chemotherapy with advanced NSCLC have been well documented, with improved quality of life and prolonged survival observed for patients with a good performance status [2, 3]. The present standard chemotherapy regimen is a platinum-containing doublet. Recently, a large trial conducted by the Eastern Cooperative Oncology Group (ECOG) compared four chemotherapy regimens in patients with advanced NSCLC [4]. Over 1000 patients were randomly assigned to receive cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. The four treatment regimens were found not to be statistically significantly different in terms of response rate or overall survival; however, toxicity was less pronounced in the carboplatin–paclitaxel arm. The median survival of all eligible patients was 7.9 months with 1- and 2-year survival rates of 33% and 11%, respectively. Other randomized trials have reported similar findings, including the recent Southwest Oncology Group (SWOG) trial (9509) and the Swedish Lung Cancer Study Group trial [5, 6]. Furthermore, the Cancer and Leukemia Group B (CALGB) recently reported results of a phase III trial (CALBG 9730) comparing combination chemotherapy (carboplatin and paclitaxel) versus single-agent chemotherapy (paclitaxel) for advanced NSCLC patients [7]. The CALGB results favor combination therapy with a platinum agent for improvement in survival, quality of life and cost-effectiveness.

Carboplatin has a more favorable toxicity profile than cisplatin, particularly with regard to non-hematological toxicities. A previous study comparing carboplatin and cisplatin-based doublet regimens demonstrated equivalent survival [8]; however, one recent randomized trial has shown superior survival with cisplatin-based chemotherapy [9]. This trial, published by Rosell et al. [9], compared cisplatin–paclitaxel with carboplatin–paclitaxel and found a statistically significant improvement in median survival in the cisplatin arm over the carboplatin arm, with survival times of 9.8 and 8.5 months, respectively. Fossella et al. [10] recently reported a randomized study of docetaxel plus either cisplatin or carboplatin versus a reference regimen of vinorelbine and cisplatin. This trial demonstrated a significant survival advantage of docetaxel and cisplatin over vinorelbine and cisplatin; however, the same benefit was not observed when docetaxel and carboplatin were compared with vinorelbine and cisplatin. These data suggest that although platinum agents are among the most active drugs in the treatment of NSCLC, there may be a difference in efficacy for various platinum drugs. The search for platinum agents, which have the same (or higher) efficacy of cisplatin, but the ease of administration and the favorable toxicity profile of carboplatin, is desirable.

Oxaliplatin is a novel antineoplastic platinum derivative with a 1,2-diaminocyclohexane-carrier ligand. Although the precise mechanism of action is unknown, platinum compounds in general are thought to exert their cytotoxic effects through the formation of DNA adducts that block both DNA replication and transcription, resulting in cell death in actively dividing cells as well as the induction of apoptosis. In vitro oxaliplatin is more potent than cisplatin, requiring fewer DNA adducts to achieve an equal level of cytotoxicity [11]. This agent has demonstrated efficacy in preclinical studies against many tumor cell lines [1216], including some that are resistant to cisplatin and carboplatin. In preclinical studies, oxaliplatin has shown additive or synergic cytotoxic properties with fluoropyrimidines, thymidylate synthase inhibitors, topoisomerase I inhibitors, microtubule inhibitors and DNA modifying/alkylating agents (cisplatin and cyclophosphamide) [17,18]. Oxaliplatin has also shown clinical activity in several solid tumors, including colorectal, ovarian, pancreatic, and head and neck cancers [2024].

The use of oxaliplatin in patients with NSCLC was studied in a phase II study by Monnet et al. [25]. In that study, single-agent oxaliplatin in chemotherapy-naïve patients with NSCLC revealed an overall single-agent response rate of 16%. The most frequently reported side-effect was acute sensory neuropathy. A phase I/II trial by the same investigators studied the combination of oxaliplatin and vinorelbine in advanced NSCLC patients [26]. Oxaliplatin was given at a fixed dose of 130 mg/m2 via a 2-h intravenous infusion on day 1, with vinorelbine at escalating doses beginning at 22 mg/m2 given via 10-min intravenous infusion on days 1 and 8, every 21 days. The primary dose-limiting toxicity noted was that of neutropenia, most often seen at the higher doses of vinorelbine. Other toxicities included grade 1 neuropathy, which represented the most frequent non-hematological toxicity observed in 24 of the 27 patients enrolled on the study. Importantly, this neurotoxicity was mild, with the majority (82%) of patients experiencing grade 1 and 2 toxicity. The overall response rate was 37%, with one patient experiencing a complete response (CR). The median duration of response for the responders was 6 months [95% confidence interval (CI) 4.5–7.4].

The aim of our trial was to combine oxaliplatin with paclitaxel as first-line chemotherapy in patients with stage IIIB (pleural effusion)/IV NSCLC. This combination has been studied previously in the phase I setting in patients with recurrent platinum-resistant ovarian cancer [27]. That study showed acceptable toxicity and significant activity in heavily pretreated patients. The activity observed seemed to be in accordance with the preclinical suggestion of the agent’s lack of cross-reactivity with other platinum compounds. The primary study objectives included defining overall response rate and time to progression. Secondary objectives included characterization of the neurotoxicity associated with the regimen, and the description of any new toxicity.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
This trial was conducted under sponsorship by the National Cancer Institute (grant U01CA63187-01) and the University of Chicago Cancer Research Center (grant CM107102-02) within the University of Chicago Phase II Network and the Ohio State University Comprehensive Cancer Center.

Eligibility
Patients with histologically or cytologically proven stage IIIB (pleural effusion)/IV NSCLC were possible candidates for this study. Disease, measurable by computed tomography (CT) scan, was required. Prior chemotherapy for NSCLC was not allowed, although prior radiotherapy and/or surgery were acceptable. Patients with brain metastases were eligible only if definitive therapy had been given. An ECOG performance status of 0, 1 or 2 at the beginning of the trial was required. Adequate organ and bone marrow function with absolute neutrophil count (ANC) ≥1500/mm3, platelet count ≥100 000/mm3, blood urea nitrogen <1.5x the upper limit of institutional normal range (ULN), creatinine <1.5x the upper limit of normal or creatinine clearance >50 ml/min, bilirubin within institutional limits of normal, and aspartate aminotransferase ≤2x ULN. Clinical evidence of pre-existing peripheral neuropathy due to comorbid conditions was an exclusion criterion. Written informed consent was obtained from all patients prior to commencing protocol treatment. Before study entry, all patients underwent evaluation consisting of complete history and physical examination, as well as a chest and upper abdomen CT scan and a bone scan. All participating institutions were required to have the treatment protocol approved by their individual institutional review boards.

Treatment plan
Protocol treatment was administered in an outpatient setting. Paclitaxel (TaxolTM) 175 mg/m2 was administered intravenously over 1 h. Oxaliplatin (EloxatinTM) 130 mg/m2 was administered intravenously over 2 h on day 1, immediately following paclitaxel. All patients received paclitaxel premedication consisting of dexamethasone 20 mg intravenously, diphenhydramine 50 mg intravenously, and famotidine or ranitidine 50 mg intravenously 30 min prior to infusion. All patients received anti-emetic therapy prior to oxaliplatin administration with ondansetron 24 mg or granisetron 2 mg by mouth 30 min prior to chemotherapy infusion. Treatment cycles were administered every 21 days.

Dose modification
Dose modification for hematological or gastrointestinal toxicity was based on the worst toxicity observed during the previous course. For grade 4 neutropenia or thrombocytopenia, the paclitaxel dose was reduced 25% in the subsequent cycle.

For grade ≥3 stomatitis/pharyngitis (oral/pharyngeal mucositis), the doses of oxaliplatin and paclitaxel were reduced by 25% in the subsequent cycle. For grade ≥3 diarrhea, the dose of oxaliplatin was reduced by 25% in the subsequent cycle. Evaluation for neurological toxicity occurred prior to each oxaliplatin and paclitaxel dose. Oxaliplatin and paclitaxel doses were reduced by 25% for significant neurotoxicity, defined as persistent grade 2 neuropathy between cycles or any grade 3 neuropathy.

Treatment evaluation
Patients were assessed for toxic effects throughout the study during formal clinic visits with a physician, at the beginning of each cycle of therapy. A specified neurological exam with a focus on sensory neuropathy was performed at each physician visit, and documented on a neurotoxicity form. The complete and differential blood counts were obtained weekly, while serum chemistries were obtained at least every 21 days.

Toxic effects were assessed in accordance with the National Cancer Institute Common Toxicity Criteria (NCI CTC), version 2.0. Neurotoxicity was graded according to an oxaliplatin-specific scale developed by the NCI CTEP. The grading system was a fusion of the WHO neuropathy grading, Sanofi grading criteria and the NCI CTC, version 2.0 (see Table 1).


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Table 1. Toxicity scale for the sensory neuropathies associated with oxaliplatin
 
Tumor response was assessed by utilizing target lesions as identified on the appropriate imaging study (CT or magnetic resonance imaging). These images were obtained every 6 weeks (two cycles) after the initiation of therapy then every 9 weeks (three cycles). A CR was defined as the complete clinical and radiographic disappearance of tumor without the appearance of new lesions. A partial response (PR) was characterized as a reduction by at least 50% of the products of the longest diameters of all measurable lesions. A PR also required that there was no growth of other lesions or the appearance of new lesions over at least 28 consecutive days. Stable disease (SD) was defined as a decrease in the sum of the products of two perpendicular diameters of all measured lesions by <50%, or an increase by <25% after a minimum of two cycles of therapy. Progressive disease (PD) was characterized as an increase in the product of the longest diameters of measured lesion by ≥25%, or the appearance of new lesions. In addition, if a target lesion was detectable on clinical examination (e.g. a dermal metastases or supraclavicular lymphadenopathy), it was measured by periodic physical examination.

Statistical analysis
The overall response rate (combining CR and PR) was computed, and a 95% CI was constructed based on the binomial distribution but ignoring the multi-stage nature of the design. Progression-free survival (defined as the time from enrolment until progression or death from any cause) and overall survival (also from date of enrolment) curves were estimated for all enrolled patients using the Kaplan–Meier method [28]. CIs for the median survival times were obtained as described previously [29, 30].


    Results
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Between November 1999 and December 2000, 38 patients were enrolled onto this study at participating hospitals of the University of Chicago Phase II Network and at the Arthur James Cancer Hospital at Ohio State University. The participating patient characteristics are listed in Table 2. A total of 181 cycles were administered, with a median number of four cycles per patient (range one to 12). All patients were assessed for toxicity and are included in the survival analysis.


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Table 2. Patient characteristics
 
Response
Thirty-six patients of the original 38 enrolled were evaluated for radiographic response (Table 3). The overall objective response rate for these 36 patients was 36.1% (95% CI 20.8% to 53.8%). This included 13 patients with a PR. No CRs were observed. The response rate for all 38 patients was 34.2% (13 of 38) (95% CI 19.6% to 51.4%). This response rate includes two patients enrolled on the study who did not undergo formal response evaluation. One of these patients had an anaphylactic reaction with the first test dose of paclitaxel, and subsequently did not receive either paclitaxel or oxaliplatin. The second patient received the first cycle of therapy, but died before the second treatment cycle was administered.


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Table 3. Response rates
 
Survival
For all patients enrolled, the median progression-free survival was 4.3 months (95% CI 2.1–6.5) with a 1-year progression free survival rate of 16%. The median overall survival for all patients was 9.2 months (95% CI 6–12.4) (Figure 1) with 1- and 2-year survival rates of 37% and 21%, respectively.



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Figure 1. Kaplan–Meier survival curve from date of first treatment (note: tick marks in graph indicate censored observations).

 
Toxicity
Hematological toxicity. Neutropenia was the predominant hematological toxicity observed. Overall, 15.7% of patients experienced grade 4 neutropenia. Febrile neutropenia was not observed. Cumulative neutropenia was responsible for five dose reductions, occurring in five separate patients. In four of these patients, neutropenia leading to a dose reduction occurred in cycle 5 (one patient), cycle 7 (two patients) and cycle 8 (one patient). One patient experienced neutropenia requiring dose reduction after cycle 1. Only one treatment delay was caused by inadequate ANC on the planned day of chemotherapy delivery. Other hematological toxicities encountered were mild to moderate, and are listed in Table 4.


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Table 4. Hematological toxicity, maximum grade for all cycles (n = 38)
 
Non-hematological toxicity. There were no grade 4 non-hematological toxicities encountered during the study. The major toxicities observed are listed in Table 5. Neurosensory toxicity was the predominant non-hematological toxicity noted. In all, 28 (73.7%) patients reported a neurosensory event during their treatment course. These toxicities were graded using the oxaliplatin-specific neurotoxicity scale. In all, six patients encountered grade 2 or higher neurotoxicity requiring dose reduction. Three patients encountered grade 3 neurotoxicity in cycle 1, and were dose-reduced for the rest of their chemotherapy cycles. The majority of the neurosensory toxicity was confined to grades 1 and 2, with only three patients (8%) experiencing grade 3. Laryngodysesthesia was observed in two patients, which was cold-induced and brief in duration.


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Table 5. Number of patients with non-hematological toxicity, maximum grade in all cycles (n = 38)
 
One patient developed an acute grade 2 hypersensitivity reaction, presumed secondary to oxaliplatin, shortly after infusion of the fourth dose. This reaction was treated with diphenhydramine and resolved completely before the patient was discharged home. The patient elected to stop treatment after this episode.

Nausea and vomiting were the next most common non-hematological toxicities and were mostly low grade; however, four patients (11%) experienced grade 3 nausea.


    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The use of a platinum-containing doublet has become standard treatment for advanced NSCLC patients with adequate performance status. We undertook this phase II trial to evaluate the response and overall survival of these patients treated with oxaliplatin, a novel platinum agent, in combination with paclitaxel. A secondary objective of this trial was to describe the toxicity of this combination.

The use of paclitaxel in patients with NSCLC is based upon previous studies demonstrating favorable results when this agent is combined with carboplatin or cisplatin. Paclitaxel/carboplatin has become a widely adopted front-line treatment regimen in the USA. This may be attributed to the ease of administration in the outpatient setting, as well as its manageable toxicity compared with cisplatin-containing regimens. Although early randomized trials reported very high response rates with this combination, the SWOG recently reported results comparing paclitaxel–carboplatin with vinorelbine–cisplatin, showing equal response rates of 27%, equivalent median survival of 8 months and equivalent 1-year survival of ~36% [5]. The recently reported CALGB study (CALGB 9730) showed similar results, with a response rate of 30%, a median survival of 8.5 months and 1-year survival rate of 36% for the carboplatin–paclitaxel arm [7]. Therefore, for the treating oncologist, side-effect profile and ease of administration remain important considerations when choosing a regimen for patients with advanced NSCLC.

The third-generation platinum drug oxaliplatin has theoretical advantages compared with older platinum drugs. First, preclinical data have shown that oxaliplatin produces cytotoxicity in platinum-resistant cell lines. Furthermore, oxaliplatin lacks the nephrotoxicity and vomiting seen with cisplatin. It also produces less myelosuppression than carboplatin. These findings make oxaliplatin a reasonable drug to study in patients with advanced NSCLC.

Our phase II experience studying oxaliplatin and paclitaxel showed the combination to be well tolerated in patients with advanced NSCLC. Although significant neurosensory toxicity was observed, it was low grade and not dose-limiting in most patients. To the investigators, the neurosensory deficits could be categorized broadly into acute or chronic deficits. The acute neurotoxicity observed was mostly peri-administration of oxaliplatin and cold-induced. Once the stimulus for the toxicity was removed the toxicity resolved. The chronic neurosensory toxicity observed was most likely attributed to that which has been previously associated with long-term paclitaxel administration, as it worsened with each succeeding cycle.

The efficacy of this paclitaxel–oxaliplatin regimen compares favorably with results from randomized trials evaluating other platinum regimens. In addition, the 1- and 2-year survival rates observed correspond to other platinum regimes studied; however, the authors recognize that the majority of patients enrolled on this trial were female, and that gender is a well-described prognostic factor [31]. In conclusion, this trial reports that the doublet of oxaliplatin and paclitaxel is an active, well tolerated and easily administered first-line therapy for patients with advanced NSCLC. Future directions to pursue with this agent could possibly focus on its integration into concomitant radiation therapy regimens for those with locally advanced disease.


    Acknowledgements
 
We thank Sylvia Watson and Kristin Hoving for research nurse support and data management, respectively. This study was supported by NCI grant U01CA63187-01, University of Chicago Cancer Research Center grant CM107102-02 and OSUCCC grant 5P30CA016058. This work was presented in part at the Thirty-ninth Annual Meeting of the American Society of Clinical Oncology, FL, 18–20 May 2002.


    FOOTNOTES
 
* Correspondence to: Dr A. M. Mauer, University of Chicago Medical Center, Department of Medicine, Section of Hematology and Oncology, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637, USA. Tel: +1-773-702-4400; Fax: +1-773-702-0963; E-mail: amauer{at}medicine.bsd.uchicago.edu Back


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 Results
 Discussion
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