International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Oncology ScandThe Concept of Personalized Medicine and the Radiation Response of Tumors By Michael L. Freeman, PhD, Senior Editor Comprehensive sequencing of tumor genomes provided the foundation for numerous preclinical studies that explored the relationship between oncogene expression and radiation sensitivity. The result is a well-validated paradigm that posits that oncogene expression can contribute to a radiation-resistant phenotype. The RAS superfamily of GTPase molecular switches was one of the first oncogene families to be examined. Using an experimental approach that used transformed NIH-3T3 cells, Sklar (1) concluded that expression of activated RAS could significantly increase radiation resistance. In subsequent years, this concept was extensively tested in preclinical assays. The data provided strong support for the hypothesis that activated K-, H-, and N-RAS could contribute to intrinsic radiation resistance (2-4). Phase 1 studies of farnesyltransferase inhibitors were undertaken and were encouraging. An excellent example is that of Hahn et al (5), who studied L-778,123 combined with standard radiation therapy (RT) for the treatment of lung and head-and-neck cancer. At a dose 1 level, this combination yielded acceptable toxicity (5). Of the 6 patients with non-small cell lung cancer (NSCLC) treated, 4 had evaluable disease and 3 of them had clinical complete responses. The fourth had a partial response. There were 3 patients with head-and-neck disease, and 2 had complete clinical responses. Interpretation of these outcomes, however, must be made with the knowledge that these patients were administered standard chemotherapy in addition to the ionizing radiation (5). Unfortunately, the most effective farnesyltransferase inhibitor, L778,123, which also can inhibit geranylgeranyl transferase, produced cardiac conduction abnormalities and was discontinued (6). Thus, the question whether RAS inhibition can radiosensitize tumors has never been tested in human phase 2 trials. The development of several new RAS inhibitors (7, 8) brings the exciting prospect that in the near future the question whether targeting of RAS can affect RT outcome will be appropriately addressed. The epidermal growth factor receptor (EGFR) family has also been the focus of extensive research. The family is composed of the receptor tyrosine kinases EGFR/ErbB1/HER 1, ErbB2/HER 2, ErbB3/HER 3, and ErbB4/HER 4. These receptors are overexpressed or mutated in many cancers, including NSCLC (60% of which overexpress EGFR) (9) and squamous cell carcinoma of the head and neck (SCCHN, 80% of which overexpress EGFR) (10). Receptor activity has been shown to be a key driver of oncogenesis (9), initiating RAS/MEK/ERK, PI3K/AKT/mTOR, and STAT Int J Radiation Oncol Biol Phys, Vol. 88, No. 3, pp. 546e548, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.09.007
signaling cascades. Approximately 10% of NSCLC patients present with activating EGFR mutations (either a L858R mutation or deletion of exon 19) that yield increased sensitivity to gefitinib or erlotinib (11). Preclinical studies have shown that molecular targeting of EGFR can result in the radiosensitization of tumor cells, thus linking the outcome of survival to a receptor’s molecular function. Clinically relevant doses of ionizing radiation can induce EGFR autophosphoryation, resulting in signaling cascades that accelerate tumor cell repopulation (12, 13). It should be mentioned that the caspase3/PGE2 apoptosis axis also contributes to accelerated repopulation (14). Additionally, irradiation causes EGFR to translocate into the nucleus, where it binds to and increases DNAdependent protein kinase catalytic subunit (DNA-PKc) activity (15). DNA PKc is an important component of nonhomologous end joining (NHEJ). As currently understood, NHEJ begins when the Ku70/80 heterodimer detects and binds to a DNA double-strand break. Binding of Ku is followed by recruitment of subsequent factors, including DNA-PKc. Next, the broken DNA ends are enzymatically processed by use of enzymes such as polynucleotide kinase/phosphatase (PNKP), exonuclease 1 (Exo1), Mre11, and Artemis. The result yields regions of DNA sequence microhomology that promote ligation reactions by DNA polymerases m and l (16). Thus, activation of EGFR can promote survival by increasing DNA repair and repopulation. Conversely, monoclonal antibody-mediated inhibition of EGFR drives irradiated cells to undergo either apoptosis (17) or senescence (18). Inhibiting EGFR activity impairs radiation-induced EGFR nuclear translocation and DNA-PKc activation, inhibits DNA repair, and increases radiosensitivity (15, 19). These preclinical results were followed by very encouraging clinical studies performed on patients with locoregionally advanced SCCHN. As stated above, the majority of patients present with elevated EGFR expression (10, 17), thus being identified as a population that could potentially benefit from targeted therapy. Reporting on 5-year survival data after a randomized phase 3 trial, Bonner et al (20) treated stage III or IV SCCHN patients for 6 to 7 weeks with comprehensive head and neck RT alone or with weekly doses of cetuximab (400 mg/m2 initial dose administered 1 week before the initiation of RT followed by 7 weekly doses at 250 mg/m2). The median overall survival for patients treated with cetuximab and RT was 49.0 months (95%
Volume 88 Number 3 2014 confidence interval, 32.8-69.5) versus 29.3 months (95% confidence interval, 20.6-41.4) in the RT-alone group. These positive results confirmed an earlier phase 2 study (21) and may be attributed to both cetuximab-mediated radiosensitization and direct molecular targeting of the disease. This Oncology Scan highlights 2 new studies on this subject. Martins et al (22) investigated the question whether the addition of the small molecule EGFR inhibitor erlotinib would benefit SCCHN patients treated with standard cisplatin-based chemoradiation therapy. Welsh et al (23) investigated the question whether the addition of erlotinib to whole-brain irradiation of patients with NSCLC brain metastasis would extend survival time.
Martins et al. Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: A randomized phase II trial. J Clin Oncol 2013. (22) Summary: In the phase 2 trial conducted by Martins et al (22), 204 stage III, IVA, and IVB SCCHN patients were randomly assigned 1 of 2 arms. Arm A patients received cisplatin (100 mg/ m2 on days 1, 22, and 43) administered during RT. Intensity modulated RT (IMRT) or 3-dimensional (3D)-accelerator-based RT was used to treat gross disease to 66 to 70 Gy in 30 to 35 fractions, 2 to 2.2 Gy per fraction, 1 fraction per day, 5 days per week. Arm B patients received cisplatin/RT plus erlotinib (150 mg/day orally or via a percutaneous endogastric tube). Erlotinib was administered 1 week before chemoradiation therapy and continued until its completion. The primary objective was complete response rate (CRR; defined by study criteria). The median follow-up time for surviving patients was 26 months. The authors concluded that erlotinib did not increase toxicity, nor did it increase CCR or progression-free survival (PFS). The key findings are as follows: 1. The addition of erlotinib did not compromise delivery of cisplatin or RT, and with 1 exception there were no common differences between the 2 arms. Patients in arm B had more rash than did those in arm A (68% vs 10%, P
Radiation Oncology biology
physics
www.redjournal.org
Oncology ScandThe Concept of Personalized Medicine and the Radiation Response of Tumors By Michael L. Freeman, PhD, Senior Editor Comprehensive sequencing of tumor genomes provided the foundation for numerous preclinical studies that explored the relationship between oncogene expression and radiation sensitivity. The result is a well-validated paradigm that posits that oncogene expression can contribute to a radiation-resistant phenotype. The RAS superfamily of GTPase molecular switches was one of the first oncogene families to be examined. Using an experimental approach that used transformed NIH-3T3 cells, Sklar (1) concluded that expression of activated RAS could significantly increase radiation resistance. In subsequent years, this concept was extensively tested in preclinical assays. The data provided strong support for the hypothesis that activated K-, H-, and N-RAS could contribute to intrinsic radiation resistance (2-4). Phase 1 studies of farnesyltransferase inhibitors were undertaken and were encouraging. An excellent example is that of Hahn et al (5), who studied L-778,123 combined with standard radiation therapy (RT) for the treatment of lung and head-and-neck cancer. At a dose 1 level, this combination yielded acceptable toxicity (5). Of the 6 patients with non-small cell lung cancer (NSCLC) treated, 4 had evaluable disease and 3 of them had clinical complete responses. The fourth had a partial response. There were 3 patients with head-and-neck disease, and 2 had complete clinical responses. Interpretation of these outcomes, however, must be made with the knowledge that these patients were administered standard chemotherapy in addition to the ionizing radiation (5). Unfortunately, the most effective farnesyltransferase inhibitor, L778,123, which also can inhibit geranylgeranyl transferase, produced cardiac conduction abnormalities and was discontinued (6). Thus, the question whether RAS inhibition can radiosensitize tumors has never been tested in human phase 2 trials. The development of several new RAS inhibitors (7, 8) brings the exciting prospect that in the near future the question whether targeting of RAS can affect RT outcome will be appropriately addressed. The epidermal growth factor receptor (EGFR) family has also been the focus of extensive research. The family is composed of the receptor tyrosine kinases EGFR/ErbB1/HER 1, ErbB2/HER 2, ErbB3/HER 3, and ErbB4/HER 4. These receptors are overexpressed or mutated in many cancers, including NSCLC (60% of which overexpress EGFR) (9) and squamous cell carcinoma of the head and neck (SCCHN, 80% of which overexpress EGFR) (10). Receptor activity has been shown to be a key driver of oncogenesis (9), initiating RAS/MEK/ERK, PI3K/AKT/mTOR, and STAT Int J Radiation Oncol Biol Phys, Vol. 88, No. 3, pp. 546e548, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.09.007
signaling cascades. Approximately 10% of NSCLC patients present with activating EGFR mutations (either a L858R mutation or deletion of exon 19) that yield increased sensitivity to gefitinib or erlotinib (11). Preclinical studies have shown that molecular targeting of EGFR can result in the radiosensitization of tumor cells, thus linking the outcome of survival to a receptor’s molecular function. Clinically relevant doses of ionizing radiation can induce EGFR autophosphoryation, resulting in signaling cascades that accelerate tumor cell repopulation (12, 13). It should be mentioned that the caspase3/PGE2 apoptosis axis also contributes to accelerated repopulation (14). Additionally, irradiation causes EGFR to translocate into the nucleus, where it binds to and increases DNAdependent protein kinase catalytic subunit (DNA-PKc) activity (15). DNA PKc is an important component of nonhomologous end joining (NHEJ). As currently understood, NHEJ begins when the Ku70/80 heterodimer detects and binds to a DNA double-strand break. Binding of Ku is followed by recruitment of subsequent factors, including DNA-PKc. Next, the broken DNA ends are enzymatically processed by use of enzymes such as polynucleotide kinase/phosphatase (PNKP), exonuclease 1 (Exo1), Mre11, and Artemis. The result yields regions of DNA sequence microhomology that promote ligation reactions by DNA polymerases m and l (16). Thus, activation of EGFR can promote survival by increasing DNA repair and repopulation. Conversely, monoclonal antibody-mediated inhibition of EGFR drives irradiated cells to undergo either apoptosis (17) or senescence (18). Inhibiting EGFR activity impairs radiation-induced EGFR nuclear translocation and DNA-PKc activation, inhibits DNA repair, and increases radiosensitivity (15, 19). These preclinical results were followed by very encouraging clinical studies performed on patients with locoregionally advanced SCCHN. As stated above, the majority of patients present with elevated EGFR expression (10, 17), thus being identified as a population that could potentially benefit from targeted therapy. Reporting on 5-year survival data after a randomized phase 3 trial, Bonner et al (20) treated stage III or IV SCCHN patients for 6 to 7 weeks with comprehensive head and neck RT alone or with weekly doses of cetuximab (400 mg/m2 initial dose administered 1 week before the initiation of RT followed by 7 weekly doses at 250 mg/m2). The median overall survival for patients treated with cetuximab and RT was 49.0 months (95%
Volume 88 Number 3 2014 confidence interval, 32.8-69.5) versus 29.3 months (95% confidence interval, 20.6-41.4) in the RT-alone group. These positive results confirmed an earlier phase 2 study (21) and may be attributed to both cetuximab-mediated radiosensitization and direct molecular targeting of the disease. This Oncology Scan highlights 2 new studies on this subject. Martins et al (22) investigated the question whether the addition of the small molecule EGFR inhibitor erlotinib would benefit SCCHN patients treated with standard cisplatin-based chemoradiation therapy. Welsh et al (23) investigated the question whether the addition of erlotinib to whole-brain irradiation of patients with NSCLC brain metastasis would extend survival time.
Martins et al. Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: A randomized phase II trial. J Clin Oncol 2013. (22) Summary: In the phase 2 trial conducted by Martins et al (22), 204 stage III, IVA, and IVB SCCHN patients were randomly assigned 1 of 2 arms. Arm A patients received cisplatin (100 mg/ m2 on days 1, 22, and 43) administered during RT. Intensity modulated RT (IMRT) or 3-dimensional (3D)-accelerator-based RT was used to treat gross disease to 66 to 70 Gy in 30 to 35 fractions, 2 to 2.2 Gy per fraction, 1 fraction per day, 5 days per week. Arm B patients received cisplatin/RT plus erlotinib (150 mg/day orally or via a percutaneous endogastric tube). Erlotinib was administered 1 week before chemoradiation therapy and continued until its completion. The primary objective was complete response rate (CRR; defined by study criteria). The median follow-up time for surviving patients was 26 months. The authors concluded that erlotinib did not increase toxicity, nor did it increase CCR or progression-free survival (PFS). The key findings are as follows: 1. The addition of erlotinib did not compromise delivery of cisplatin or RT, and with 1 exception there were no common differences between the 2 arms. Patients in arm B had more rash than did those in arm A (68% vs 10%, P
