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In Reply:

Hygeia Hospital, Athens, Greece

The use of preclinical evidence in designing chemotherapy combinations and schedules is not without value. However, it is generally accepted that cell line and preclinical data have their limitations in their ability to accurately model the clinical picture. To imply that the clinical value of concurrent schedules of gemcitabine and paclitaxel may be limited on the basis of a preclinical study of gemcitabine and docetaxel may be overly speculative, particularly in light of the evidence from both preclinical and multiple clinical trials of gemcitabine and paclitaxel in non–small-cell lung cancer (NSCLC).

In the case of the combination of gemcitabine with paclitaxel in the preclinical setting, Kroep et al¹ studied gemcitabine and paclitaxel administered simultaneously or with 4- and 24-hour intervals using Lewis Lung, H460, and H322 NSCLC cell lines. Both sequences were examined: gemcitabine before paclitaxel, and paclitaxel before gemcitabine. The authors concluded that "growth inhibition of the combination was not more than additive, irrespective of treatment schedule."¹ Although the authors noted that there is insufficient evidence to conclude that the apoptotic index has prognostic value in predicting clinical response, the authors speculated that this sequence might be more favorable on the basis of the observation that the administration of paclitaxel before gemcitabine induced a higher apoptotic index in NSCLC cells. This sequence recommendation is consistent with that used in the present study.²

In addition to preclinical evidence, there are now a large number of phase II trials investigating the combination of gemcitabine and paclitaxel at various doses, administered in both sequences, and on multiple different schedules. Douillard et al³ treated 54 chemotherapy-naive patients with stages IIIb and IV NSCLC with paclitaxel 200 mg/m² as a 3-hour infusion before gemcitabine 1,000 mg/m² as a 30-minute infusion on day 1 of a 21-day cycle. Gemcitabine was administered alone on day 8. The response rate seen in 47 assessable patients was 36.2%. This rate is similar to that seen in a phase II trial by Bhatia et al,⁴ who treated 42 chemotherapy-naive patients with stages IIIb and IV NSCLC with gemcitabine 1,000 mg/m² as a 30-minute infusion administered before paclitaxel 110 mg/m² as a 1-hour infusion on days 1, 8, and 15 of a 28-day cycle. In 34 patients assessable for response, the response rate was 38.2%.

The above-mentioned phase II trials are in concordance with the results seen in the present study, with a response rate in the gemcitabine and paclitaxel arm of 35%. Hence, the applicability of the preclinical results to clinical practice can be questioned on the basis of the results of phase II and III trials that have shown that the combination of gemcitabine and paclitaxel or docetaxel are equivalent to platinum-containing doublets.^2,5 These equivalent results and the well-recognized fact that platinum doublets are superior to single agents in the treatment of advanced NSCLC^6–10 make us wonder why Dr. Castro thinks that the results of our study are a "disappointing demonstration of antagonism."

Whether the discordance between the potential antagonism between gemcitabine and taxanes seen in some preclinical models and the positive clinical results obtained by the combinations of gemcitabine and either paclitaxel or docetaxel is because antagonism does not exist in clinical practice or because of the administration of an additional dose of gemcitabine on day 8, as was the case in our study, remains to be determined.

We recommend the investigation of the best schedule and the best sequence to deliver this and other combinations of drugs. Such investigations may be initially based on preclinical studies, but the results should always be confirmed in clinical trials, ideally in a randomized setting.

REFERENCES

1. Kroep JR, Giaccone G, Tolis C, et al: Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines. Br J Cancer 83:1069–1076, 2000[CrossRef][Medline]

2. Kosmidis P, Mylonakis N, Nicolaides C, et al: Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: A phase III randomized trial. J Clin Oncol 20:3578–3585, 2002[Abstract/Free Full Text]

3. Douillard J, Lerouge D, Monnier A, et al: Combined paclitaxel and gemcitabine as first-line treatment in metastatic non-small cell lung cancer: A multicentre phase II study. Br J Cancer 84:1179–1184, 2001[CrossRef][Medline]

4. Bhatia S, Hanna N, Ansari R, et al: A phase II study of weekly gemcitabine and paclitaxel in patients with previously untreated stage IIIb and IV non-small cell lung cancer. Lung Cancer 38:73–77, 2002[CrossRef][Medline]

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

6. Sandler AB, Nemunaitis J, Denham C, et al: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 18:122–130, 2000[Abstract/Free Full Text]

7. Sederholm C: Gemcitabine compared with gemcitabine plus carboplatin in advanced non-small cell lung cancer: A phase III study by the Swedish Lung Cancer Study Group. Proc Am Soc Clin Oncol 21:A1162, 2002 (abstr 1162)

8. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: A Southwest Oncology Group study. J Clin Oncol 16:2459–2465, 1998[Abstract]

9. Lilenbaum RC, Herndon J, List M, et al: Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): A CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol 21:A2, 2002 (abstr 2)

10. Le Chevalier T, Brisgand D, Soria JC, et al: Long term analysis of survival in the European randomized trial comparing vinorelbine/cisplatin to vindesine/cisplatin and vinorelbine alone in advanced non-small cell lung cancer. Oncologist 6:8–11, 2001 (suppl 1)[Abstract/Free Full Text]

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