Annals of Oncology 15:1298-1299, 2004
© 2004 European Society for Medical Oncology
Reply to the article "Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study", by Groen et al. (Ann Oncol 2004; 15: 427–432)
I read with great interest the recent article by Groen et al. [1
] in which continuously infused (CI) carboplatin (CBDCA) during continuous course of radical radiation therapy (RT) did not improve results over that obtained with the same RT given alone in patients with locally unresectable non-small-cell lung cancer (NSCLC). Although this study cannot be compared directly with earlier studies using CBDCA with RT in this disease [2–5] with regard to total RT dose, lack of administration of the second drug (etoposide), the mode of administration of chemotherapy (CHT) (bolus versus CI) and no elective mediastinal RT, all of which are likely explanations for the inferiority of the former regimen. It is, nevertheless, tempting to speculate about additional possible causes of the different outcomes of this and other studies. This is especially the case since the authors neither used local recurrence-free survival and distant metastasis-free survival as end points, nor provided patterns of failure for the two arms. Also, slight (P=?) imbalance in important prognostic factors favoring the RT alone group (more females and more stage IIIA patients) was not corrected for using the multivariate analysis.
Perhaps prolonged low plasma levels of CBDCA after CI were not enough to reach the necessary level of radioenhancement, as presumably was the case with brief bolus administration of CBDCA (and etoposide), also considered as ‘low-dose daily CHT’. Perhaps also the timing of low and sustained levels of CBDCA relative to RT was less critical and its influence less pronounced than the timing of bolus administration of CBDCA in other studies relative to RT, since it is likely that sublethal damage repair after daily fraction(s) of RT is a major cellular event that takes place in studies using concurrent RT and CHT. It is clear that without combining proper pharmacokinetic and pharmacodynamic studies with preclinical, radiobiology studies through translational approach, mechanism-based studies, the optimal interaction between RT and CHT would remain unknown, a goal clearly identified several years ago by the National Cancer Institute [6].
Whatever the underlying principle of RT–CHT interaction, this study was, for a number of years in its life as an abstract, considered only as a negative one. I consider it to be also a positive one, owing to the fact that it reconfirmed that (i) low-dose CHT is a low toxicity approach when given concurrently with high dose RT [3,5], (ii) that extra CHT dose provided during weekends of CI are probably not conferring any impact on treatment outcome, as has already proved to be the case with somewhat higher doses of CHT given using weekend CHT (combined with daily low-dose CHT [5]), and (iii) that single-agent CBDCA is insufficient to sensitize RT, as previously shown by the Cancer and Leukemia Group B 9130 study [7], although with preceding induction CHT.
Finally, a more general remark regarding the statement in the conclusions that ‘induction CHT followed by RT is one of standards in this disease’. This is not so! Not so at least in the last several years, in which we have witnessed that concurrent RT and CHT is superior to induction CHT followed by RT [8,9]. Why it is still widely practised worldwide is a matter of not accepting evidence-based medicine, at the expense of the patients suffering from this disease.
International Atomic Energy Agency, Vienna, Austria
Email: b.jeremic{at}iaea.org
References
1. Groen HJM, van der Leest AHW, Fokkema E et al. Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study. Ann Oncol 2004; 15: 427–432.
2. Jeremic B, Shibamoto Y, Acimovic L et al. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. J Clin Oncol 1995; 13: 452–458.
3. Jeremic B, Shibamoto Y, Acimovic L et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: A randomized study. J Clin Oncol 1996; 14: 1065–1070.
4. Jeremic B, Shibamoto Y, Milicic B et al. Concurrent radiochemotherapy for patients with stage III non-small cell lung cancer (NSCLC). Long-term results of a phase II study. Int J Radiat Oncol Biol Phys 1998; 42: 1091–1096.[CrossRef][ISI][Medline]
5. Jeremic B, Shibamoto Y, Acimovic LJ et al. Hyperfractionated radiation therapy and concurrent low-dose, daily carboplatin/etoposide with or without week-end carboplatin/etoposide chemotherapy in stage III non-small-cell lung cancer: a randomized trial. Int J Radiat Oncol Biol Phys 2001; 50: 19–25.[CrossRef][ISI][Medline]
6. Coleman NC, Cumberlin RL. Translational research in radiation oncology. Int J Radiat Oncol Biol Phys 2001; 49: 885–890.[CrossRef][Medline]
7. Clamon G, Herndon J, Cooper R et al. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol 1999; 17: 4–11.
8. Furuse K, Nishikawa H, Takada Y et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999; 17: 2692–2699.
9. Curran WJ Jr, Scott C, Langer C et al. Phase III comparison of sequential Vs concurrent chemoradiation for pts with unresected stage III non-small cell lung cancer (NSCLC): Initial report of Radiation Therapy Oncology Group (RTOG) 9410. Proc Am Soc Clin Oncol 2000; 19.
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