Is cisplatin still the best platinum compound in non-small-cell lung cancer?

J.-C. Soria and T. Le Chevalier

Institut Gustave Roussy, 39, rue Camille Desmoulins, F-94805 Villejuif Cedex, France (E-mail: tle-che@igr.fr)

Lung cancer remains the leading cause of cancer-related death in industrialized countries and is therefore a major health problem for western societies [1]. In the past, the role of chemotherapy for non-small-cell lung cancer (NSCLC) has been extensively debated and the lack of activity of most cytotoxic compounds, used as single agents or in combination, led a large part of the medical community to refute chemotherapy for patients with NSCLC. Nevertheless, anecdotical reports and occasional prospective studies suggested a potential benefit of chemotherapy in advanced NSCLC in the 1970s.

In fact, the era of chemotherapy in NSCLC began with the introduction of cisplatin in this setting, despite studies suggesting a poorly encouraging activity/toxicity ratio [2]. First generation phase III studies using cisplatin-based doublets reported encouraging and sometimes statistically significant survival benefits when compared with best supportive care (BSC) [3]. However, it took almost 20 years and the means of different literature meta-analyses to prove that cisplatin-based chemotherapy confers a modest but definitive and statistically significant survival benefit in NSCLC as compared with BSC [4, 5]. The overview conducted jointly by the British Medical Research Council Cancer Trials Office and the Institut Gustave Roussy, using updated individual patient data from 52 trials performed between 1961 and 1991, clarified the role of chemotherapy in NSCLC [6]. The studies on cisplatin-based chemotherapy provided most data (>50%) and the strongest evidence for an effect in favor of chemotherapy. In the advanced setting, the overall hazard ratio with cisplatin-based drugs was 0.73 (P <0.0001), which was equivalent to an absolute survival benefit of 10% at 1 year, with a 95% confidence interval of 5% to 15%.

Interestingly, and in spite of the well established toxicity of cisplatin, quality of life, when studied, appeared improved since specific symptom relief overshadowed the proper side effects of cisplatin [7]. As a result, cisplatin-based regimens have been the mainstay of chemotherapy in NSCLC. Nevertheless, cisplatin has a low therapeutic ratio, with significant toxicities including severe nausea and vomiting, renal toxicity requiring adequate hydration, ototoxicity and neuropathy. Substantial improvements in the management of cisplatin-induced toxicities (emesis and nephrotoxicity) have been achieved [8, 9], but ototoxicity and neuropathy remain unpredictable, inconstantly reversible and are not always clearly dose-dependent. Cisplatin analogs have been developed to help circumvent some of these toxicities; among them, carboplatin, which was introduced in clinical trials in the early 1980s, is still the leading compound. Carboplatin has very limited nephrotoxicity and neurotoxicity, as well as a mild ematogenic effect. In fact, myelosuppression and particularly thrombocytopenia is the dose-limiting toxicity of carboplatin. Carboplatin-based chemotherapy in locally advanced and metastatic NSCLC has been widely used, in particular in the USA, as an alternative to cisplatin-based chemotherapy in order to minimize clinical toxicities [10]. Despite its debatable equivalent activity, carboplatin has been increasingly used because it can be delivered conveniently as a short 1-h infusion, and therefore on an outpatient basis. These practical considerations have contributed to the widespread use of this drug in replacement of cisplatin.

In this issue of Annals of Oncology, Rosell et al. elegantly report the results of a large European randomized study comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with inoperable NSCLC [11]. This is the first randomized trial directly comparing cisplatin and carboplatin, in combination with a 3-h paclitaxel infusion, at the same dose and schedule in both arms. This paper is of special interest since carboplatin/paclitaxel is probably the most widely used combination for NSCLC in the USA and the reference arm for USA collaborative groups such as Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) [10, 12, 13]. The primary end point of the present trial was to show a non-inferiority in response rate for paclitaxel/carboplatin compared with paclitaxel/cisplatin. Briefly, the populations in each arm were comparable, and the response rate, the main objective, was 25% with paclitaxel/carboplatin and 28% with paclitaxel/cisplatin (P = 0.45). Nevertheless, median progression-free survival time and median survival time were significantly higher in the paclitaxel/cisplatin arm compared with the paclitaxel/carboplatin arm [4.8 months versus 3 months (P = 0.035), and 9.8 months versus 8.2 months (P = 0.019), respectively]. There was no advantage of paclitaxel/carboplatin in terms of tolerance or quality of life (QLQ-C30 and LC-13 scales). The authors therefore conclude that paclitaxel/cisplatin must be preferred to paclitaxel/carboplatin, at least in patients able to receive cisplatin. The observed differences favoring cisplatin cannot be explained by imbalances in patient characteristics or the number of cycles received. Only an area under the curve (AUC) of 4.9 (instead of the planned AUC of 6, which is recommended in this setting) is to be highlighted in 34% of the patients because of miscalculation of AUC at the initial cycles. The significantly superior survival achieved with cisplatin in this large European randomized trial is in contrast to the results reported in a similar, recently published United States study [12]. The four-arm ECOG trial included 1207 patients. It compared paclitaxel (as a 24-h infusion)/cisplatin with paclitaxel (as a 3-h infusion)/carboplatin, and gemcitabine/cisplatin as well as docetaxel/cisplatin. The survival rates for the four groups were 31%, 34%, 36% and 31%, respectively, at 1 year and 10%, 11%, 13% and 11%, respectively, at 2 years. No significant advantage in terms of survival of one group over the others was observed. Median survival was 7.8 months in the paclitaxel/cisplatin arm compared with 8.1 months in the paclitaxel/carboplatin arm. Toxicities were similar in the four groups. The discrepancies between the EU and the USA trial could be related to differences in dosage, schedule, and infusion time of paclitaxel and cisplatin [11, 12]. In this regard, a 24-h infusion of paclitaxel has occasionally been described as superior to a 3-h infusion in terms of tumor response [14]. An additional potential explanation for the differences observed between the EU and the USA trials could be the population characteristics in terms of histological subtypes. Interestingly, while the proportion of squamous cell carcinoma is 38% in the study reported by Rosell et al., this information is not provided in the ECOG study [11, 12]. This remark is important because recent studies have suggested differences in response rate and risk of progressive disease depending on the histological subtype as well as the specific treatment combination used (i.e. patients with non-adenocarcinoma tumors could be more sensitive to cisplatin/docetaxel than patients with an adenocarcinoma subtype) [15]. The data presented by Rosell et al. are, however, in line with another large randomized trial comparing docetaxel/cisplatin with docetaxel/carboplatin and vinorelbine/cisplatin, which reported a significantly superior median survival time in the docetaxel/cisplatin arm (10.9 months) [16].

Altogether, the present work by Rosell et al. contributes significantly to the debate regarding the therapeutic efficacy of carboplatin as compared with cisplatin in lung cancer. Carboplatin does not possess equivalent activity to cisplatin in all platinum-sensitive tumors. It is now clear that carboplatin is inferior to cisplatin in germ cell, head and neck, oesophageal and probably lung cancer [1721]. On the other hand, cisplatin remains a cumbersome agent requiring heavy pretreatment hydration of patients and therefore a hospital stay of several hours or even overnight. Numerous patients with NSCLC requiring chemotherapy have contraindications to the use of cisplatin, such as inability to receive hyperhydration (cardiac dysfunction, superior venous cava syndrome) or previous neurological or hearing problems. In such cases, carboplatin may be an alternative to cisplatin, which remains the cornerstone of chemotherapy in NSCLC in 2002. Nevertheless, one must stress that a therapeutic ceiling has been reached in NSCLC with standard chemotherapeutic agents, whether they are cisplatin based or not. In this respect, the present work confirms the recent ECOG and SWOG trials showing a 1-year survival in advanced NSCLC of around 30% to 40% [22]. New treatment strategies are needed to overcome the therapeutic limits reached with conventional chemotherapeutic drugs. This can be achieved by identifying novel therapeutic targets that are related to the distinctive properties of cancer cells.

In a seminal paper, Hanahan and Weinberg enumerated the hallmarks of cancer as being: self-sufficiency in growth signals, insensitivity to anti-growth signals, limitless replicative potential, evasion of apoptosis, sustained angiogenesis, and tissue invasion and metastasis [23]. Each of these characteristics can be targeted at the molecular level through the use of novel biological agents interacting on specific cancer pathways. Monoclonal antibodies, protein kinase inhibitors, farnesyltransferase inhibitors and antiangiogenic agents are some of the new promising agents. At all stages of lung cancer, there exists the opportunity to use novel targeted biological agents either alone or in combination with standard modalities of treatment. At the moment, much hope is based on the combination of molecular targeted therapies with standard chemotherapy in the setting of locally advanced and metastatic NSCLC [24, 25].

J.-C. Soria & T. Le Chevalier

Institut Gustave Roussy, 39, rue Camille Desmoulins, F-94805 Villejuif Cedex, France (E-mail: tle-che@igr.fr)

References

1. Jemal A, Thomas A, Murray T et al. Cancer statistics, 2002. CA Cancer J Clin 2002; 52: 23–47.[Abstract/Free Full Text]

2. Guarino AM, Miller DS, Arnold TS et al. Platinate toxicity: past, present and prospects. Cancer Treat Rep 1979; 63: 1475–1483.[ISI][Medline]

3. Rapp E, Pater JL, Willan A et al. Chemotherapy can prolong survival in patients with adavanced non-small cell lung cancer: report of a Canadian multicenter randomized trial. J Clin Oncol 1988; 6: 633–641.[Abstract]

4. Marino P, Pamapallona S, Preatoni A, Cantoni A, Invernezzi F. Chemotherapy versus best supportive care in advanced non-small cell lung cancer: results of a meta-analysis of the literature. Chest 1994; 106: 861–865.[Abstract]

5. Souquet PJ, Chauvin F, Boissel JP et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993; 342: 19–21.[ISI][Medline]

6. 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 randomized clinical trials. Br Med J 1995; 311: 899–909.[Abstract/Free Full Text]

7. Bunn PA, Kelly K. New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res 1998; 4: 1087–1100.[Abstract]

8. Marty M, Pouillart P, Scholl S et al. Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR38032F) with high-dose metoclopramide in control of cisplatin induced emesis. N Engl J Med 1990; 322: 846–848.[ISI][Medline]

9. Daugaard G, Abildgaard U. Cisplatin nephrotoxicity. Cancer Chemother Pharmacol 1989; 25: 1–9.[ISI][Medline]

10. Shyr Y, Choy H, Cmelak A et al. Pattern of practice survey: non-small cell lung cancer in the US. Proc Am Soc Clin Oncol 1998; 17: 463a (Abstr 1778).

11. Rosell R, Gatzemeier U, Betticher DC et al. Phase III randomised trial comparing paclitaxel/carboplatin versus paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol 2002; 13: 1539–1549.[Abstract/Free Full Text]

12. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002; 346: 92–98.[Abstract/Free Full Text]

13. Kelly K, Crowley J, Bunn PA et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001; 19: 3210–3218.[Abstract/Free Full Text]

14. Rowinsky EK. The taxanes: dosing and scheduling considerations. Oncology 1997; 11 (Suppl 2): 1–13.

15. Georgoulias V, Papadakis E, Alexopoulous A et al. Platinum-based and non-platinum based chemotherapy in advanced non-small cell lung cancer: a randomised multicentre trial. Lancet 2001; 357: 1478–1484.[ISI][Medline]

16. Rodriguez J, Pawel A, Pluzanska A et al. A multicenter, randomized phase III study of docetaxel + cisplatin (DC) and docetaxel + carboplatin (DCB) vs vinorelbine + cisplatin (VC) in chemotherapy-naïve patients with advanced and metastatic non-small cell lung cancer. Proc Am Soc Clin Oncol 2001; 20: 314a (Abstr 1252).

17. Lokich J, Anderson N. Carboplatin versus cisplatin in solid tumors: an analysis of the literature. Ann Oncol 1998; 9: 13–21.[Abstract]

18. Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cispatin and carboplatin. J Clin Oncol 1999; 17: 409–422.[Abstract/Free Full Text]

19. Bokemeyer C, Kohrmann O, Tischler J et al. A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide and bleomycin (CEB) for patients with good-risk metastatic non-seminatous germ cell tumors. Ann Oncol 1996; 7: 1015–1021.[Abstract]

20. De Andres L, Brunet J, Lopez-Pausa A et al. Randomized trial of neoadjuvant cisplatin and fluorouracil versus carboplatin and fluorouracil in patients with stage IV-M0 head and neck cancer. J Clin Oncol 1995; 13: 1493–1500.[Abstract]

21. Kelsen D, Atiq OT. Therapy of upper gastrointestinal tract cancers. Curr Probl Cancer 1991; 15: 237–294.

22. Kelly K, Crowley J, Bunn PA et al. A randomized phase III trial of paclitaxel plus cisplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001; 19: 3210–3218.[Abstract/Free Full Text]

23. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70.[ISI][Medline]

24. Yuen A, Halsey J, Fisher G et al. Phase I/II trial of ISIS 3521, an antisense inhibitor of PKC-alpha, with carboplatin and paclitaxel in non-small cell lung cancer. Proc Am Soc Clin Oncol 2001; 20: 309a (Abstr 1234).

25. Perez-Soler R, Chachoua A, Huberman M et al. A Phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy, in patients (pts) with advanced, EGFR-expressing, non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001; 20: 310a (Abstr 1235).