Reply to the article "Editorial comment on ‘Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: an EORTC double-blind placebo-controlled phase III study’", by P. A. Bunn Jr (Ann Oncol 2001; 12: 1339–1340)

V. C. G. Tjan-Heijnen1, P. E. Postmus2 and A. Ardizzoni for the European Organisation for Research and Treatment of Cancer, Lung Cancer Group3

1University Medical Centre Nijmegen, Nijmegen, The Netherlands; 2Vrije Universiteit Medical Centre, Amsterdam, The Netherlands; 3Istituto Nationale per la Ricerca sul Cancro, Genova, Italy (E-mail: V.Tjan@onco.azn.nl)

We would like to comment on the editorial by P. A. Bunn in the October 2001 issue of the Annals of Oncology [1], concerning our randomised phase III trial published in the same issue [2]. In this study, patients with chemo-naïve small-cell lung cancer (SCLC) were randomised to receive prophylactic antibiotics (ciprofloxacin 750 mg, plus roxithromycin 150 mg bd on days 4–13) or placebo, to assess the impact of prophylaxis on the incidence of febrile leucopenia (FL). Half of the patients were treated with standard three-weekly CDE chemotherapy (cyclophosphamide, doxorubicin and etoposide) and half of the patients with intensified two-weekly CDE (2 x 2 factorial design) to assess the impact of dose intensification on survival (n = 240 patients). The randomisation between prophylactic antibiotics and placebo was stopped prematurely (n = 163 patients), as recommended by an Independent Data Monitoring Committee. Prophylactic ciprofloxacin plus roxithromycin during CDE chemotherapy reduced the incidence of FL, the number of infections, the use of therapeutic antibiotics and hospitalisations due to FL by ~50%, with a reduced number of deaths due to infection. It was concluded that for patients with a similar risk of FL the prophylactic use of antibiotics should be considered (in the placebo arm of the trial there was at least one episode of FL in 43% of patients).

Dr Bunn’s comments are on three points:

The choice of chemotherapy.
The role of prophylactic antibiotics.
The cost-effectiveness of prophylactic antibiotics.

Dr Bunn’s remark regarding the choice of chemotherapy is not relevant for the conclusion of our paper. In addition, CDE still remains one of the most widely used chemotherapy regimen for SCLC treatment in Europe [3] and is the standard reference arm for the EORTC Lung Group.

Secondly, Dr Bunn states that the data do not justify the prophylactic use of these antibiotics in any SCLC patients, at least not if the intensified CDE arm does not show a major survival benefit over standard-dose CDE. We reported at the last meeting of the American Society of Clinical Oncology in May 2001, that survival was not improved by intensified CDE [4]. Despite this lack of survival benefit in the intensified CDE arm, we still consider our conclusion to be valid. In other words, in patients with increased risk for FL (with or without CDE, with or without SCLC) the prophylactic use of antibiotics should be considered.

Indeed, Dr Bunn is correct in saying that the benefit of prophylaxis was almost exclusively seen in the intensified CDE arm, although the quoted figures were wrong (they are: 29% in the standard/placebo arm, compared with 24% in the standard/prophylaxis arm; and 56% in the intensified/placebo arm, compared with 24% in the intensified/prophylaxis arm). Unfortunately, we had insufficient power to test a possible interaction between the efficacy of prophylaxis and the dose-intensity of chemotherapy. The only valid conclusion that can be drawn from our study is that in the total study population of 163 patients, prophylactic antibiotics reduced the incidence of FL from 43% to 24% (P = 0.007). Importantly, the baseline risk for FL tended to be increased not only with intensified chemotherapy (P = 0.07), but also in elderly patients >=60 years (P = 0.043) and in patients with extensive disease (P = 0.007). Of note, only those patients with an excellent performance status (0–1) were included in this study, while from the literature it is known that the risk of FL is increased in patients with performance status >=2 [5]. So we adhere to our conclusion, that in patients with increased risk for FL, by whatever cause, the prophylactic use of antibiotics is effective and should therefore be considered.

Furthermore, it is stated that prophylaxis is expensive. On the contrary, we have demonstrated that giving oral prophylactic antibiotics to SCLC patients undergoing chemotherapy is the dominant strategy, demonstrating both cost-savings, due to fewer hospitalisations for FL, and superior efficacy [6].

Finally, we agree that the next goal is to further clarify the precise selection criteria for using antibiotic prophylaxis, e.g. based on tumour type, chemotherapy regimen, age, extent of disease and performance status.

V. C. G. Tjan-Heijnen1, P. E. Postmus2, A. Ardizzoni3, for the European Organisation for Research and Treatment of Cancer, Lung Cancer Group

1University Medical Centre Nijmegen, Nijmegen, The Netherlands; 2Vrije Universiteit Medical Centre, Amsterdam, The Netherlands; 3Istituto Nationale per la Ricerca sul Cancro, Genova, Italy (E-mail: V.Tjan@onco.azn.nl)

References

References

1. Bunn PA. Editorial comments on ‘Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: an EORTC double-blind placebo-controlled phase III study’. Ann Oncol 2001; 12: 1339–1340.[ISI][Medline]

2. Tjan-Heijnen VCG, Postmus PE, Ardizzoni A et al. Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: an EORTC double-blind placebo-controlled phase III study. Ann Oncol 2001; 12: 1359–1368.[Abstract]

3. Sambrook RJ, Girling DJ. A national survey of the chemotherapy regimens used to treat small-cell lung cancer (SCLC) in the United Kingdom. Br J Cancer 2001; 84: 1447–1452.[ISI][Medline]

4. Tjan-Heijnen VCG, Ardizzoni A, Postmus PE et al. Dose-intensification of cyclophosphamide, doxorubicin and etoposide (CDE)-chemotherapy does not improve survival in small cell lung cancer (SCLC): final results of a randomized phase III EORTC study. J Clin Oncol 2001; 20: A1379.

5. Morittu L, Earl HM, Souhami RL et al. Patients at risk of chemotherapy-associated toxicity in small-cell lung cancer. Br J Cancer 1989; 59: 801–804.[ISI][Medline]

6. Caleo S, Tjan-Heijnen VCG, Gorlia T et al. Comparing the results of cost-effectiveness analyses conducted in Germany (D) and The Netherlands (Nl) for antibiotica prophylaxis in small-cell lung cancer (SCLC) patients. Eur J Cancer 2000; 36: S12.





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