Letter to the Editor
Concurrent Hyperfractionated Radiation Therapy and Low Dose, Daily Chemotherapy as an Effective and Low Toxicity Approach in Locally Advanced (Stage III) NoneSmall-Cell Lung Cancer Branislav Jeremic Clinical Lung Cancer, Vol. 15, No. 3, e31-2 ª 2014 Elsevier Inc. All rights reserved.
Dear Sir, I read with great interest the systematic review by Koning et al,1 comparing various concurrent radiation therapy (RT)chemotherapy (CHT) regimens in locally advanced nonesmallcell lung cancer. The authors should be applauded for their elegant and always timely work that reconfirmed the long-standing belief of thoracic oncologists that high-dose RT and high-dose CHT is the recipe for high-grade toxicity. When, however, lower doses of either cisplatin or carboplatin were used, the rates of hematological and nonhematological toxicity were much lower. In particular, the authors identified low-dose cisplatin as the preferred treatment to be given concurrently with RT, based on laboratory2 and clinical data3 that suggest its advantage over other modes of administration. Eligibility criteria in the study of Koning et al1 excluded 5 of our clinical trials4-8 with a total of 600 patients using hyperfractionated (Hfx) RT and concurrent low-dose CHT, and, therefore, many more patients than all 5 enrolled carboplatinbased studies in their report. Nevertheless, results of our studies could only support findings of Koning et al1 in that low-dose daily CHT leads to lower toxicity than high dose CHT. In particular, 1 of our prospective randomized studies7 showed that adding more CHT (in a way of “weekend” CHT as we have used it) to concurrent RT and daily CHT led to nothing but increased toxicity. In contrast, outcomes of our specific treatment regimens in which Hfx RT was used with somewhat shorter interfraction intervals (IFIs) of 4.5 to 6.0 hours, and CHT was given between the 2 daily fractions4-8 were the following:
Division of Radiation Oncology, Stellenbosch University and the Tygerberg Hospital, Cape Town, South Africa Submitted: Sep 9, 2013; Accepted: Sep 17, 2013; Epub: Nov 16, 2013
1525-7304/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2013.09.006
1. Hyperfractionated RT and concurrent low-dose daily CHT is an effective treatment approach with 5-year survivals of > 20% and the median survival times of > 20 months. 2. These results were accompanied with very low acute and late high-Grade ( 3) toxicity with no Grade 5 toxicities observed in any of the 600 treated patients (5-year data). 3. Incidence of hematological and nonhematological highGrade toxicities is at least comparable with those observed in single-agent studies, showing that adding a second drug via low-dose daily administration is not hazardous. 4. Adding a second agent might provide additional synergistic effects with respect to the first CHT agent and RT, respectively, leading to better outcomes because it can be observed by comparing our results with results of studies that used for example, single-agent carboplatin. 5. A particularity of our approach might have included the administration of both drugs between the 2 daily fractions, enabling more synergistic (enhancing) effects of low-dose CHT and twice daily RT. 6. Similar to the previous items listed, a somewhat shorter IFI (4.5-5.0 hours) were shown in several of our analyses as an approach advantageous over longer IFIs (5.5-6.0 hours) regarding local control and survival. 7. Our low-dose daily CHT might have enabled better and longer (continuous) exposure of both drugs to daily RT, and in our case, to daily fractions leading to better radioenhancement as can be observed with improved local level in our studies, similar to the European Organization for the Research and Treatment of Cancer study that used daily cisplatin.3 Taken together, evidence now clearly exists that the preferred treatment approach is RT and low-dose, daily CHT. As Koning et al1 rightly identify, there is a necessity to further optimize concurrent RT-CHT including, perhaps, novel, targeted agents. Thoracic oncologists should continue to have their clinical research
Clinical Lung Cancer May 2014
- e31
Letter to the Editor imperative unchanged and optimize what works (ie, concurrent RTCHT), and not what does not work (eg, induction or consolidation drug therapy).
References 1. Koning CC, Wouterse SJ, Daams JG, Uitterhoeve LL, van den Heuvel MM, Belderbos JS. Toxicity of concurrent radiochemotherapy for locally advanced nonesmall-cell lung cancer: a systematic review of the literature. Clin Lung Cancer 2013; 14:481-7. 2. Bartelink H, Kallman RF, Rapacchietta D, Hart GA. Therapeutic enhancement in mice by clinically relevant dose and fractionation schedules of cisdiamminedichloroplatinum (II) and irradiation. Radiother Oncol 1986; 6:61-74. 3. Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable nonesmall-cell lung cancer. N Engl J Med 1992; 326:524-30.
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4. Jeremic B, Shibamoto Y, Acimovic LJ, et al. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III nonesmall-cell lung cancer. J Clin Oncol 1995; 13:452-8. 5. Jeremic B, Shibamoto Y, Acimovic LJ, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III nonesmall-cell lung cancer: a randomized study. J Clin Oncol 1996; 14:1065-70. 6. Jeremic B, Shibamoto Y, Milicic B, et al. Concurrent radiochemotherapy for patients with stage III nonesmall-cell lung cancer (NSCLC). Long-term results of a phase II study. Int J Radiat Oncol Biol Phys 1998; 42:1091-6. 7. 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 nonesmall-cell lung cancer: a randomized trial. Int J Radiat Oncol Biol Phys 2001; 50:19-25. 8. Jeremic B, Milicic B, Acimovic LJ, et al. Concurrent hyperfractionated radiotherapy and low-dose daily carboplatin/paclitaxel in patients with stage III nonesmall-cell lung cancer (NSCLC). Long-term results of a phase II study. J Clin Oncol 2005; 23: 1144-51.
Concurrent Hyperfractionated Radiation Therapy and Low Dose, Daily Chemotherapy as an Effective and Low Toxicity Approach in Locally Advanced (Stage III) NoneSmall-Cell Lung Cancer Branislav Jeremic Clinical Lung Cancer, Vol. 15, No. 3, e31-2 ª 2014 Elsevier Inc. All rights reserved.
Dear Sir, I read with great interest the systematic review by Koning et al,1 comparing various concurrent radiation therapy (RT)chemotherapy (CHT) regimens in locally advanced nonesmallcell lung cancer. The authors should be applauded for their elegant and always timely work that reconfirmed the long-standing belief of thoracic oncologists that high-dose RT and high-dose CHT is the recipe for high-grade toxicity. When, however, lower doses of either cisplatin or carboplatin were used, the rates of hematological and nonhematological toxicity were much lower. In particular, the authors identified low-dose cisplatin as the preferred treatment to be given concurrently with RT, based on laboratory2 and clinical data3 that suggest its advantage over other modes of administration. Eligibility criteria in the study of Koning et al1 excluded 5 of our clinical trials4-8 with a total of 600 patients using hyperfractionated (Hfx) RT and concurrent low-dose CHT, and, therefore, many more patients than all 5 enrolled carboplatinbased studies in their report. Nevertheless, results of our studies could only support findings of Koning et al1 in that low-dose daily CHT leads to lower toxicity than high dose CHT. In particular, 1 of our prospective randomized studies7 showed that adding more CHT (in a way of “weekend” CHT as we have used it) to concurrent RT and daily CHT led to nothing but increased toxicity. In contrast, outcomes of our specific treatment regimens in which Hfx RT was used with somewhat shorter interfraction intervals (IFIs) of 4.5 to 6.0 hours, and CHT was given between the 2 daily fractions4-8 were the following:
Division of Radiation Oncology, Stellenbosch University and the Tygerberg Hospital, Cape Town, South Africa Submitted: Sep 9, 2013; Accepted: Sep 17, 2013; Epub: Nov 16, 2013
1525-7304/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2013.09.006
1. Hyperfractionated RT and concurrent low-dose daily CHT is an effective treatment approach with 5-year survivals of > 20% and the median survival times of > 20 months. 2. These results were accompanied with very low acute and late high-Grade ( 3) toxicity with no Grade 5 toxicities observed in any of the 600 treated patients (5-year data). 3. Incidence of hematological and nonhematological highGrade toxicities is at least comparable with those observed in single-agent studies, showing that adding a second drug via low-dose daily administration is not hazardous. 4. Adding a second agent might provide additional synergistic effects with respect to the first CHT agent and RT, respectively, leading to better outcomes because it can be observed by comparing our results with results of studies that used for example, single-agent carboplatin. 5. A particularity of our approach might have included the administration of both drugs between the 2 daily fractions, enabling more synergistic (enhancing) effects of low-dose CHT and twice daily RT. 6. Similar to the previous items listed, a somewhat shorter IFI (4.5-5.0 hours) were shown in several of our analyses as an approach advantageous over longer IFIs (5.5-6.0 hours) regarding local control and survival. 7. Our low-dose daily CHT might have enabled better and longer (continuous) exposure of both drugs to daily RT, and in our case, to daily fractions leading to better radioenhancement as can be observed with improved local level in our studies, similar to the European Organization for the Research and Treatment of Cancer study that used daily cisplatin.3 Taken together, evidence now clearly exists that the preferred treatment approach is RT and low-dose, daily CHT. As Koning et al1 rightly identify, there is a necessity to further optimize concurrent RT-CHT including, perhaps, novel, targeted agents. Thoracic oncologists should continue to have their clinical research
Clinical Lung Cancer May 2014
- e31
Letter to the Editor imperative unchanged and optimize what works (ie, concurrent RTCHT), and not what does not work (eg, induction or consolidation drug therapy).
References 1. Koning CC, Wouterse SJ, Daams JG, Uitterhoeve LL, van den Heuvel MM, Belderbos JS. Toxicity of concurrent radiochemotherapy for locally advanced nonesmall-cell lung cancer: a systematic review of the literature. Clin Lung Cancer 2013; 14:481-7. 2. Bartelink H, Kallman RF, Rapacchietta D, Hart GA. Therapeutic enhancement in mice by clinically relevant dose and fractionation schedules of cisdiamminedichloroplatinum (II) and irradiation. Radiother Oncol 1986; 6:61-74. 3. Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable nonesmall-cell lung cancer. N Engl J Med 1992; 326:524-30.
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Clinical Lung Cancer May 2014
4. Jeremic B, Shibamoto Y, Acimovic LJ, et al. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III nonesmall-cell lung cancer. J Clin Oncol 1995; 13:452-8. 5. Jeremic B, Shibamoto Y, Acimovic LJ, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III nonesmall-cell lung cancer: a randomized study. J Clin Oncol 1996; 14:1065-70. 6. Jeremic B, Shibamoto Y, Milicic B, et al. Concurrent radiochemotherapy for patients with stage III nonesmall-cell lung cancer (NSCLC). Long-term results of a phase II study. Int J Radiat Oncol Biol Phys 1998; 42:1091-6. 7. 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 nonesmall-cell lung cancer: a randomized trial. Int J Radiat Oncol Biol Phys 2001; 50:19-25. 8. Jeremic B, Milicic B, Acimovic LJ, et al. Concurrent hyperfractionated radiotherapy and low-dose daily carboplatin/paclitaxel in patients with stage III nonesmall-cell lung cancer (NSCLC). Long-term results of a phase II study. J Clin Oncol 2005; 23: 1144-51.
