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Adding cetuximab to stereotactic radiotherapy for non-small cell lung cancer might reduce local failure rates
Medical Hypotheses 78 (2012) 420–422
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Adding cetuximab to stereotactic radiotherapy for non-small cell lung cancer might reduce local failure rates Carsten Nieder a,b,⇑, Nicolaus Andratschke c a
Department of Oncology and Palliative Medicine, Nordland Hospital, Bodø, Norway Institute of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway c Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany b
a r t i c l e
i n f o
Article history: Received 12 August 2011 Accepted 4 January 2012
a b s t r a c t Encouraging results have been obtained with stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC). However, local control rates decrease in larger volume disease. Several studies have found a correlation between T stage or tumor volume and local progression-free survival. In many cases with larger tumor volume, sufficiently high radiation doses can not be administered because the tolerance of surrounding normal tissues must be respected. Under such circumstances, simultaneous administration of radiosensitizing agents, which increase tumor cell kill, might improve the therapeutic ratio. Based on sound preclinical evidence and recent data from patients with stage III NSCLC and head and neck cancer, we hypothesize that cetuximab might be an investigational agent that merits further evaluation. The aim of prospective studies of SBRT and cetuximab would be to examine the toxicity profile of the drug in combination with high-dose hypofractionated thoracic radiotherapy and eventually to prove the superiority of combined treatment over SBRT alone. If improved local control rates could be observed, overall survival might improve accordingly. Ó 2012 Elsevier Ltd. All rights reserved.
Background Non-small cell lung cancer (NSCLC) is among the leading causes of cancer death in the western world. Survival of patients diagnosed with advanced disease has remained disappointing despite some gradual improvement. Patients with stage I disease have the highest chance for cure. Though still the gold standard for treatment of stage I NSCLC, surgery as the sole curative approach has recently been challenged by hypofractionated stereotactic body radiation therapy (SBRT). Studies performed by several institutions described high local control, low mediastinal failure rates and good disease-specific survival [1–4]. With the ability to deliver high biologically effective doses (BED) equivalent to more than 100 Gy in 2-Gy fractions, local control rates rise to over 80% depending on tumor size [1,3,5] compared to approximately 50% in historical series treated with conventional fractionated radiotherapy (summarized in [4]). Guckenberger et al. have recently analysed dose–response relationships in a combined group of patients with NSCLC or lung metastases treated with SBRT [6]. The BED to the clinical target ⇑ Corresponding author at: Department of Oncology and Palliative Medicine, Nordland Hospital, P.O. Box 1480, 8092 Bodø, Norway. Tel.: +47 75 57 8490; fax: +47 75 53 4975. E-mail address: [email protected] (C. Nieder). 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2012.01.001
volume (CTV) based on 4D dose calculation and an alpha/beta ratio of 10 Gy was closely correlated with local control. At 3 years, local control was 89% and 62% for >100 Gy and <100 Gy BED. As most of the irradiated patients in these SBRT series were not eligible for surgery due to their significant comorbidity, overall survival is considerably lower as compared to surgical series. The prevailing causes of death after SBRT are cardiovascular and pulmonal comorbidity, as well as second primary cancers. The encouraging results with regard to local control have prompted several prospective trials for stage I/II NSCLC comparing SBRT to surgical resection in operable patients (Radiation Therapy Oncology Group (RTOG) 0236 phase II trial, USA; ROSEL phase III trial [Radiosurgery Or Surgery for Early Lung Cancer], The Netherlands). Results from these studies are eagerly awaited. Even with SBRT, radiation is more efficacious in sterilizing smaller tumor volumes. In larger volume disease, local control rates decrease. In our recent study, patients with T2 disease had inferior actuarial local control (77% at 3 years) [4]. In fact, all local failures were observed in patients with T2 tumors. Other studies have also found a correlation between T stage and local progression free survival [7,8]. In many cases with larger tumor volume, high BED above the threshold of 100 Gy in 2-Gy fractions cannot be administered because the tolerance of surrounding normal tissues must be respected. Under such circumstances, simultaneous administration of radiosensitizing agents that increase tumor cell
C. Nieder, N. Andratschke / Medical Hypotheses 78 (2012) 420–422
kill might improve the therapeutic ratio, provided these agents do not sensitize critical normal tissues in the same fashion. Hypothesis: cetuximab increases the efficacy of radiotherapy in patients with NSCLC The RTOG has recently published a phase II study of chemoradiotherapy with carboplatin and paclitaxel plus cetuximab in patients (n = 87) with stage III NSCLC (RTOG 0324) [9]. From the loading dose of cetuximab to the end of the consolidation phase, 17 weekly treatments with this antibody targeting the epidermal growth factor receptor (EGFR) were administered. EGFR is often over expressed in NSCLC and preclinical data provide a rationale for interfering with EGFR pathways in NSCLC [10–12]. The radiation dose was 63 Gy in 35 fractions and chemotherapy was administered concurrently and in the consolidation phase. The authors concluded that treatment was feasible and survival longer than any previously reported by the RTOG. Median survival was 22.7 months and 2-year survival 49%. A confirmatory intergroup phase III trial is currently ongoing. A Swedish phase II study (n = 71) in stage III NSCLC used induction chemotherapy (cisplatin/docetaxel) followed by radiation (68 Gy) and 8 infusions of cetuximab [13]. Again, treatment was feasible and survival promising (2-year rate 37%). Histology had no significant influence on survival. A German phase II study included only patients unfit for chemoradiotherapy who received radiotherapy and cetuximab (n = 30), including a 13-week maintenance period [14]. Median survival was 19.5 months. Histologic NSCLC subtype did not impact on survival. Historically, the added value of cetuximab has been proven in a pivotal head and neck cancer radiotherapy trial [15]. As in the NSCLC trials, conventional radiation fractions in the order of 2 Gy administered 5 times weekly were used. However, higher daily radiation doses have been used in patients with recurrent head and neck cancer treated with fractionated stereotactic re-irradiation. Unger et al. administered a median of 5 fractions of 6 Gy in patients treated with (n = 11) or without cetuximab and basically observed acute grade I–III toxicities, which were expected in such patient populations treated with re-irradiation [16]. Heron et al. compared 2 groups of patients with recurrent head and neck cancer treated with stereotactic radiotherapy alone (n = 35) or with additional cetuximab (n = 35) [17]. The median dose was 40 Gy in 5 fractions (maximum 44 Gy in 5 fractions in 18 cases). They found an overall survival advantage without a significant increase in grade III/IV toxicities. Only 3 patients had acute grade III toxicities. Pre-clinical data have shown that cetuximab increases tumor radiocurability also when single fraction radiation was used [18]. Discussion Under experimental laboratory conditions in animal models, cetuximab increases tumor radiocurability (fractionated and single dose irradiation) [12,18]. Clinically, this effect has been confirmed in head and neck cancer (phase III data with fractionated irradiation) [15]. No phase III data are yet available for NSCLC and radiotherapy administered in larger than conventional fractions. However, smaller head and neck cancer re-irradiation studies suggest that cetuximab can be combined with 5 fractions of 6–8 Gy without obvious increase in serious toxicity [16,17]. It appears therefore possible to study hypofractionated cetuximab-enhanced SBRT regimens in patients with NSCLC if the ongoing intergroup study confirms the usefulness of this drug in patients with more advanced disease. With SBRT the major toxicity concerns include damage to esophagus, lungs, large blood vessels, thoracic wall and brachial plexus [19,20,2]. At least regarding esophageal and
421
lung toxicity, previous NSCLC studies suggest that conventional fractionated radiotherapy can safely be combined with cetuximab [9,13,14]. These studies also suggest that inclusion of any histologic type of NSCLC should be considered. A recent internet search (http://www.clinicaltrials.gov, accessed 13th of July 2011) has not shown any registered studies of SBRT plus cetuximab for NSCLC. The initial strategy might be to consider patients with larger volume T2 disease for this experimental approach, given that patients with T1 disease rarely fail locally. The optimal duration of treatment is presently unknown. SBRT is completed much faster than conventional radiotherapy given over 6–7 weeks. Even with conventional irradiation, the RTOG and the German study included maintenance cetuximab after the concomitant phase however for different time periods [9,14]. Prospective head to head comparisons are required to establish the optimal duration of treatment and to avoid unnecessary cost and toxicity related to prolonged drug therapy. A recent analysis of a phase III study (BMS099; taxane/carboplatin with or without cetuximab; no radiotherapy) where tumor samples from 225 patients were examined, did not find significant associations between KRAS and EGFR and various outcome parameters [21]. However, it is important to conduct comparable biomarker analyses in NSCLC treated with radiotherapy and cetuximab-based regimens. By doing so, we might be able to find out whether all patients with NSCLC have a chance to benefit from the addition of cetuximab or tailored approaches should be preferred. Local control is a prerequisite for cure and long-term survival in patients with non-metastatic NSCLC, even in the elderly and frail, and innovative strategies to improve this important endpoint are warranted [22–26]. It is clear that radiation delivered in a short overall treatment time, with the aim of overcoming tumor cell repopulation, is more efficacious than prolonged fractionation regimens [27]. The Maastricht University group has performed treatment planning studies comparing different fractionation schedules [28]. Five treatment plans were compared, dependent on the normal tissue dose constraints (classic fractionation with 2 Gy per day, 5 days/week, vs. hypofractionated vs. hyperfractionated accelerated with or without individualized maximal tolerable dose prescription). The latter schedule consisted of 1.8 Gy twice daily. The estimated tumor control probability increased most (by 26%) with hyperfractionated accelerated radiotherapy using an individualized maximal tolerable dose prescription, accepting for example a maximal mean lung dose of 19 Gy and/or maximal spinal cord dose of 54 Gy. Clinical data in stage III patients suggest favorable survival after such individualized isotoxic accelerated radiotherapy (median 23.6 months in patients who received additional sequential chemotherapy and not reached (2-year survival 67%) in those who received concurrent chemotherapy) [29]. These figures compare favorably with the results of the cetuximab studies discussed earlier [9,13,14]. Thus, hypofractionation is not the only way to increase survival rates in NSCLC. Another issue to consider is development of distant metastases, which also compromises survival, in patients treated with SBRT for early-stage NSCLC [30–33]. Certain risk groups might benefit from addition of systemic chemotherapy comparable to the treatment algorithm in surgically treated patients [34,35]. However, age and comorbidity might prevent many of the typical SBRT patients from tolerating sequential post-radiation chemotherapy. In conclusion, the hypothesis put forward here could be tested in prospective clinical trials, which eventually might contribute to better treatment results in patients with NSCLC.
Conflict of interest statement No conflict of interest exists.
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C. Nieder, N. Andratschke / Medical Hypotheses 78 (2012) 420–422
References [1] Fakiris AJ, McGarry RC, Yiannoutsos CT, et al. Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 2009;75:677–82. [2] Chang JY, Balter PA, Dong L, et al. Stereotactic body radiation therapy in centrally and superiorly located stage I or isolated recurrent non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;72:967–71. [3] Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 2009;27:3290–6. [4] Andratschke N, Zimmermann F, Boehm E, et al. Stereotactic radiotherapy of histologically proven inoperable stage I non-small cell lung cancer: patterns of failure. Radiother Oncol 2011;101:245–9. [5] Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S. Outcomes of riskadapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;70:685–92. [6] Guckenberger M, Wulf J, Mueller G, et al. Dose-response relationship for image-guided stereotactic body radiotherapy of pulmonary tumors: relevance of 4D dose calculation. Int J Radiat Oncol Biol Phys 2009;74:47–54. [7] Bral S, Gevaert T, Linthout N, et al. Prospective, risk-adapted strategy of stereotactic body radiotherapy for early-stage non-small-cell lung cancer: results of a phase II trial. Int J Radiat Oncol Biol Phys 2011;80:1343–9. [8] Chi A, Liao Z, Nguyen NP, Xu J, Stea B, Komaki R. Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage non-small-cell lung cancer: clinical implications. Radiother Oncol 2010;94:1–11. [9] Blumenschein Jr GR, Paulus R, Curran WJ, et al. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. J Clin Oncol 2011;29:2312–8. [10] Raben D, Helfrich B, Chan DC, et al. The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res 2005;11:795–805. [11] Andratschke NH, Dittmann KH, Mason KA, et al. Epidermal growth factor receptor as a target to improve treatment of lung cancer. Clin Lung Cancer 2004;5:340–52. [12] Milas L, Fan Z, Andratschke NH, Ang KK. Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys 2004;58:966–71. [13] Hallqvist A, Wagenius G, Rylander H, et al. Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: satellite – a phase II study from the Swedish Lung Cancer Study Group. Lung Cancer 2011;71:166–72. [14] Jensen AD, Münter MW, Bischoff HG, et al. Combined treatment of nonsmall cell lung cancer stage III with intensity-modulated radiotherapy and cetuximab: the NEAR trial. Cancer 2011;117:2986–94. [15] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21–8. [16] Unger KR, Lominska CE, Deeken JF, et al. Fractionated stereotactic radiosurgery for reirradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys 2010;77:1411–9. [17] Heron DE, Rwigema JC, Gibson MK, Burton SA, Quinn AE, Ferris RL. Concurrent cetuximab with stereotactic body radiotherapy for recurrent squamous cell carcinoma of the head and neck: a single institution matched case-control study. Am J Clin Oncol 2011;34:165–72. [18] Nasu S, Ang KK, Fan Z, Milas L. C225 antiepidermal growth factor receptor antibody enhances tumor radiocurability. Int J Radiat Oncol Biol Phys 2001;51:474–7.
[19] Nagata Y, Wulf J, Lax I, et al. Stereotactic radiotherapy of primary lung cancer and other targets: results of consultant meeting of the International Atomic Energy Agency. Int J Radiat Oncol Biol Phys 2011;79:660–9. [20] De Ruysscher D, Faivre-Finn C, Nestle U, et al. European Organisation for Research and Treatment of cancer recommendations for planning and delivery of high-dose, high-precision radiotherapy for lung cancer. J Clin Oncol 2010;28:5301–10. [21] Khambata-Ford S, Harbison CT, Hart LL, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:918–27. [22] Wurstbauer K, Weise H, Deutschmann H, et al. Non-small cell lung cancer in stages I-IIIB: long-term results of definitive radiotherapy with doses P80 Gy in standard fractionation. Strahlenther Onkol 2010;186:551–7. [23] Machtay M, Bae K, Movsas B, et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced nonsmall cell lung carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2012;82:425–34. [24] Guckenberger M, Wilbert J, Richter A, Baier K, Flentje M. Potential of adaptive radiotherapy to escalate the radiation dose in combined radiochemotherapy for locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2011;79:901–8. [25] Anderson CS, Curran WJ. Combined modality therapy for stage III non-smallcell lung cancer. Semin Radiat Oncol 2010;20:186–91. [26] Onishi H, Shirato H, Nagata Y, et al. Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery? Int J Radiat Oncol Biol Phys 2011;81:1352–8. [27] De Ruysscher D, Reymen B, van Baardwijk A. High-dose hyperfractionated accelerated radiotherapy in non-small cell lung cancer. Minerva Chir 2011;66:341–5. [28] Van Baardwijk A, Bosmans G, Bentzen SM, et al. Radiation dose prescription for non-small-cell lung cancer according to normal tissue dose constraints: an in silico clinical trial. Int J Radiat Oncol Biol Phys 2008;71:1103–10. [29] De Ruysscher D, van Baardwijk A, Steevens J, et al. Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long-term survival of patients with stage III NSCLC: a prospective populationbased study. Radiother Oncol 2011. [30] Grills IS, Mangona VS, Welsh R, et al. Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer. J Clin Oncol 2010;28:928–35. [31] Baumann P, Nyman J, Lax I, et al. Factors important for efficacy of stereotactic body radiotherapy of medically inoperable stage I lung cancer. A retrospective analysis of patients treated in the Nordic countries. Acta Oncol 2006;45:787–95. [32] Burdick MJ, Stephans KL, Reddy CA, Djemil T, Srinivas SM, Videtic GM. Maximum standardized uptake value from staging FDG-PET/CT does not predict treatment outcome for early-stage non-small-cell lung cancer treated with stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 2010;78:1033–9. [33] Oshiro Y, Aruga T, Tsuboi K, et al. Stereotactic body radiotherapy for lung tumors at the pulmonary hilum. Strahlenther Onkol 2010;186:274–9. [34] Sangha R, Price J, Butts CA. Adjuvant therapy in non-small cell lung cancer: current and future directions. Oncologist 2010;15:862–72. [35] NSCLC Meta-analyses Collaborative Group, Arriagada R, Auperin A, Burdett S, et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010;375:1267–77.
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Adding cetuximab to stereotactic radiotherapy for non-small cell lung cancer might reduce local failure rates Carsten Nieder a,b,⇑, Nicolaus Andratschke c a
Department of Oncology and Palliative Medicine, Nordland Hospital, Bodø, Norway Institute of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway c Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany b
a r t i c l e
i n f o
Article history: Received 12 August 2011 Accepted 4 January 2012
a b s t r a c t Encouraging results have been obtained with stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC). However, local control rates decrease in larger volume disease. Several studies have found a correlation between T stage or tumor volume and local progression-free survival. In many cases with larger tumor volume, sufficiently high radiation doses can not be administered because the tolerance of surrounding normal tissues must be respected. Under such circumstances, simultaneous administration of radiosensitizing agents, which increase tumor cell kill, might improve the therapeutic ratio. Based on sound preclinical evidence and recent data from patients with stage III NSCLC and head and neck cancer, we hypothesize that cetuximab might be an investigational agent that merits further evaluation. The aim of prospective studies of SBRT and cetuximab would be to examine the toxicity profile of the drug in combination with high-dose hypofractionated thoracic radiotherapy and eventually to prove the superiority of combined treatment over SBRT alone. If improved local control rates could be observed, overall survival might improve accordingly. Ó 2012 Elsevier Ltd. All rights reserved.
Background Non-small cell lung cancer (NSCLC) is among the leading causes of cancer death in the western world. Survival of patients diagnosed with advanced disease has remained disappointing despite some gradual improvement. Patients with stage I disease have the highest chance for cure. Though still the gold standard for treatment of stage I NSCLC, surgery as the sole curative approach has recently been challenged by hypofractionated stereotactic body radiation therapy (SBRT). Studies performed by several institutions described high local control, low mediastinal failure rates and good disease-specific survival [1–4]. With the ability to deliver high biologically effective doses (BED) equivalent to more than 100 Gy in 2-Gy fractions, local control rates rise to over 80% depending on tumor size [1,3,5] compared to approximately 50% in historical series treated with conventional fractionated radiotherapy (summarized in [4]). Guckenberger et al. have recently analysed dose–response relationships in a combined group of patients with NSCLC or lung metastases treated with SBRT [6]. The BED to the clinical target ⇑ Corresponding author at: Department of Oncology and Palliative Medicine, Nordland Hospital, P.O. Box 1480, 8092 Bodø, Norway. Tel.: +47 75 57 8490; fax: +47 75 53 4975. E-mail address: [email protected] (C. Nieder). 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2012.01.001
volume (CTV) based on 4D dose calculation and an alpha/beta ratio of 10 Gy was closely correlated with local control. At 3 years, local control was 89% and 62% for >100 Gy and <100 Gy BED. As most of the irradiated patients in these SBRT series were not eligible for surgery due to their significant comorbidity, overall survival is considerably lower as compared to surgical series. The prevailing causes of death after SBRT are cardiovascular and pulmonal comorbidity, as well as second primary cancers. The encouraging results with regard to local control have prompted several prospective trials for stage I/II NSCLC comparing SBRT to surgical resection in operable patients (Radiation Therapy Oncology Group (RTOG) 0236 phase II trial, USA; ROSEL phase III trial [Radiosurgery Or Surgery for Early Lung Cancer], The Netherlands). Results from these studies are eagerly awaited. Even with SBRT, radiation is more efficacious in sterilizing smaller tumor volumes. In larger volume disease, local control rates decrease. In our recent study, patients with T2 disease had inferior actuarial local control (77% at 3 years) [4]. In fact, all local failures were observed in patients with T2 tumors. Other studies have also found a correlation between T stage and local progression free survival [7,8]. In many cases with larger tumor volume, high BED above the threshold of 100 Gy in 2-Gy fractions cannot be administered because the tolerance of surrounding normal tissues must be respected. Under such circumstances, simultaneous administration of radiosensitizing agents that increase tumor cell
C. Nieder, N. Andratschke / Medical Hypotheses 78 (2012) 420–422
kill might improve the therapeutic ratio, provided these agents do not sensitize critical normal tissues in the same fashion. Hypothesis: cetuximab increases the efficacy of radiotherapy in patients with NSCLC The RTOG has recently published a phase II study of chemoradiotherapy with carboplatin and paclitaxel plus cetuximab in patients (n = 87) with stage III NSCLC (RTOG 0324) [9]. From the loading dose of cetuximab to the end of the consolidation phase, 17 weekly treatments with this antibody targeting the epidermal growth factor receptor (EGFR) were administered. EGFR is often over expressed in NSCLC and preclinical data provide a rationale for interfering with EGFR pathways in NSCLC [10–12]. The radiation dose was 63 Gy in 35 fractions and chemotherapy was administered concurrently and in the consolidation phase. The authors concluded that treatment was feasible and survival longer than any previously reported by the RTOG. Median survival was 22.7 months and 2-year survival 49%. A confirmatory intergroup phase III trial is currently ongoing. A Swedish phase II study (n = 71) in stage III NSCLC used induction chemotherapy (cisplatin/docetaxel) followed by radiation (68 Gy) and 8 infusions of cetuximab [13]. Again, treatment was feasible and survival promising (2-year rate 37%). Histology had no significant influence on survival. A German phase II study included only patients unfit for chemoradiotherapy who received radiotherapy and cetuximab (n = 30), including a 13-week maintenance period [14]. Median survival was 19.5 months. Histologic NSCLC subtype did not impact on survival. Historically, the added value of cetuximab has been proven in a pivotal head and neck cancer radiotherapy trial [15]. As in the NSCLC trials, conventional radiation fractions in the order of 2 Gy administered 5 times weekly were used. However, higher daily radiation doses have been used in patients with recurrent head and neck cancer treated with fractionated stereotactic re-irradiation. Unger et al. administered a median of 5 fractions of 6 Gy in patients treated with (n = 11) or without cetuximab and basically observed acute grade I–III toxicities, which were expected in such patient populations treated with re-irradiation [16]. Heron et al. compared 2 groups of patients with recurrent head and neck cancer treated with stereotactic radiotherapy alone (n = 35) or with additional cetuximab (n = 35) [17]. The median dose was 40 Gy in 5 fractions (maximum 44 Gy in 5 fractions in 18 cases). They found an overall survival advantage without a significant increase in grade III/IV toxicities. Only 3 patients had acute grade III toxicities. Pre-clinical data have shown that cetuximab increases tumor radiocurability also when single fraction radiation was used [18]. Discussion Under experimental laboratory conditions in animal models, cetuximab increases tumor radiocurability (fractionated and single dose irradiation) [12,18]. Clinically, this effect has been confirmed in head and neck cancer (phase III data with fractionated irradiation) [15]. No phase III data are yet available for NSCLC and radiotherapy administered in larger than conventional fractions. However, smaller head and neck cancer re-irradiation studies suggest that cetuximab can be combined with 5 fractions of 6–8 Gy without obvious increase in serious toxicity [16,17]. It appears therefore possible to study hypofractionated cetuximab-enhanced SBRT regimens in patients with NSCLC if the ongoing intergroup study confirms the usefulness of this drug in patients with more advanced disease. With SBRT the major toxicity concerns include damage to esophagus, lungs, large blood vessels, thoracic wall and brachial plexus [19,20,2]. At least regarding esophageal and
421
lung toxicity, previous NSCLC studies suggest that conventional fractionated radiotherapy can safely be combined with cetuximab [9,13,14]. These studies also suggest that inclusion of any histologic type of NSCLC should be considered. A recent internet search (http://www.clinicaltrials.gov, accessed 13th of July 2011) has not shown any registered studies of SBRT plus cetuximab for NSCLC. The initial strategy might be to consider patients with larger volume T2 disease for this experimental approach, given that patients with T1 disease rarely fail locally. The optimal duration of treatment is presently unknown. SBRT is completed much faster than conventional radiotherapy given over 6–7 weeks. Even with conventional irradiation, the RTOG and the German study included maintenance cetuximab after the concomitant phase however for different time periods [9,14]. Prospective head to head comparisons are required to establish the optimal duration of treatment and to avoid unnecessary cost and toxicity related to prolonged drug therapy. A recent analysis of a phase III study (BMS099; taxane/carboplatin with or without cetuximab; no radiotherapy) where tumor samples from 225 patients were examined, did not find significant associations between KRAS and EGFR and various outcome parameters [21]. However, it is important to conduct comparable biomarker analyses in NSCLC treated with radiotherapy and cetuximab-based regimens. By doing so, we might be able to find out whether all patients with NSCLC have a chance to benefit from the addition of cetuximab or tailored approaches should be preferred. Local control is a prerequisite for cure and long-term survival in patients with non-metastatic NSCLC, even in the elderly and frail, and innovative strategies to improve this important endpoint are warranted [22–26]. It is clear that radiation delivered in a short overall treatment time, with the aim of overcoming tumor cell repopulation, is more efficacious than prolonged fractionation regimens [27]. The Maastricht University group has performed treatment planning studies comparing different fractionation schedules [28]. Five treatment plans were compared, dependent on the normal tissue dose constraints (classic fractionation with 2 Gy per day, 5 days/week, vs. hypofractionated vs. hyperfractionated accelerated with or without individualized maximal tolerable dose prescription). The latter schedule consisted of 1.8 Gy twice daily. The estimated tumor control probability increased most (by 26%) with hyperfractionated accelerated radiotherapy using an individualized maximal tolerable dose prescription, accepting for example a maximal mean lung dose of 19 Gy and/or maximal spinal cord dose of 54 Gy. Clinical data in stage III patients suggest favorable survival after such individualized isotoxic accelerated radiotherapy (median 23.6 months in patients who received additional sequential chemotherapy and not reached (2-year survival 67%) in those who received concurrent chemotherapy) [29]. These figures compare favorably with the results of the cetuximab studies discussed earlier [9,13,14]. Thus, hypofractionation is not the only way to increase survival rates in NSCLC. Another issue to consider is development of distant metastases, which also compromises survival, in patients treated with SBRT for early-stage NSCLC [30–33]. Certain risk groups might benefit from addition of systemic chemotherapy comparable to the treatment algorithm in surgically treated patients [34,35]. However, age and comorbidity might prevent many of the typical SBRT patients from tolerating sequential post-radiation chemotherapy. In conclusion, the hypothesis put forward here could be tested in prospective clinical trials, which eventually might contribute to better treatment results in patients with NSCLC.
Conflict of interest statement No conflict of interest exists.
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