Targeted Oncology
Targeted Oncology
Targeted Oncology

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Safety and Efficacy of Combination Targeted Therapy and Radiotherapy

Danielle S. Bitterman, BA, and Kevin L. Du, MD, PhD, MSCI
Published Online: Mar 09,2017

Abstract


Targeted cancer therapies that act on specific drivers of oncogenesis are rapidly entering clinical use. While many of these agents are ineffective at improving cure rates as monotherapy, there is ample preclinical evidence that they are both chemosensitizing and radiosensitizing, and can improve cure rates when utilized in combination treatment regimens. There is therefore a need for high-quality safety and efficacy data on targeted therapy in combination with radiation therapy (RT). This article reviews the currently published clinical trials examining the combination of RT with commonly used targeted agents, such as vascular endothelial growth factor inhibitors, endothelial growth factor receptor inhibitors, and inhibitors of the PI3K/Akt/mTOR pathway. Continued efforts to develop high-quality clinical trial data combining targeted agents with RT are necessary for patient safety and to improve clinical outcomes.
 

Introduction


Radiation therapy (RT), together with surgery and chemotherapy, is one of the primary modalities used in definitive and palliative cancer treatment. Utilization analyses have revealed that RT is a part of initial treatment in approximately 30% of patients with cancer,1 and approximately 50% of patients overall receive RT.2 In comparing contribution toward cure by treatment modality, a European Union expert panel determined that cure is achieved in 49% of patients by surgery, 40% by RT, and 11% by chemotherapy.3 Given these statistics and in light of advancements expanding the clinical indications of RT, RT will continue to be an essential modality in the treatment of malignancies in the future.

Targeted cancer agents that block specific molecular pathways involved in oncogenesis are rapidly shifting the landscape of cancer treatment. While these agents present promising opportunities for the treatment of many malignancies, the majority are cytostatic, and many impart modest, if any, survival benefit as monotherapy.4,5 However, there is preclinical evidence that these agents are radiosensitizing and may improve cure rates when used in combination with RT.

The radiosensitizing effects of classical chemotherapeutics, including cisplatin, 5-fluorouracil (5-FU), taxanes, and temozolomide, have been well characterized, and the combination of such agents with RT has been demonstrated to improve survival and cure rates across many cancer types in randomized clinical trials.6-18 Since these agents are nonspecific and radiosensitize normal tissue, such treatment carries greater toxicity. While this toxicity is accepted due to the even greater clinical benefit, targeted agents present an exciting opportunity because they may selectively radiosensitize tumor cells without a concomitant increase in normal tissue toxicity. In this review, we summarize the currently published clinical trials of commonly used therapies in combination with RT, with attention to data on efficacy and toxicity.
 

Hormone Therapy


Androgen-deprivation therapy (ADT) in combination with RT for prostate cancer can be viewed as an early targeted biologic approach. In 1997, the seminal Southwest Oncology Group (SWOG)/European Organization for Research and Treatment of Cancer (EORTC) randomized trial demonstrated improved survival with the addition of goserelin to definitive RT for locally advanced prostate cancer.17 Grade 3 or above acute and late toxicities were not significantly different with the addition of ADT. However, combined late grade 1-3 toxicities, including urinary incontinence and urethral stricture, were significantly increased in patients treated with ADT. Despite the higher rate of adverse effects (AEs) of combined therapy, this toxicity was deemed acceptable, and ADT with RT is currently an accepted standard of care for locally advanced prostate cancer.
 

Monoclonal Antibodies


Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGF-A), is a pioneering targeted agent that has been studied in large clinical trials.19 A recently published phase III trial utilizing bevacizumab with temozolamide and RT in glioblastoma multiforme improved progression- free survival (PFS) and quality-of-life endpoints, but not overall survival (OS).20 The rates of grade 3 AEs were increased with the addition of bevacizumab. Interestingly, these toxicities were not primarily radiation-related. Instead, the majority were attributable to bevacizumab, and included thromboembolic events, bleeding events, impaired wound healing, gastrointestinal (GI) perforation, and congenital heart failure. Specifically, the rate of cerebral hemorrhage was increased in patients treated with bevacizumab compared with placebo (3.3% vs 2.0%). In rectal cancer, several early trials demonstrated the feasibility of using bevacizumab in combination with chemoradiation, with overall similar rates of AEs compared with historical controls. 21-24 However, increased GI bleeding thought to be due to the addition of bevacizumab was also observed in these studies.

For example, a phase II study from Canada reported severe preoperative bleeding events in 17% of patients treated with combination bevacizumab and chemoradiation.23 In pancreatic cancer, two phase II trials evaluating the addition of bevacizumab to chemoradiation did not improve survival outcomes compared with historical rates.25,26 Several bleeding events were noted with the addition of bevacizumab, but the sites of bleeding were outside of the radiation field. Ultimately, further studies are needed to determine the safety and efficacy of bevacizumab with chemoradiation and its application in the treatment of malignancies. Nevertheless, the data appear to support acceptable, though perhaps increased, toxicities of bleeding and thromboembolic events attributable specifically to bevacizumab.




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Safety and Efficacy of Combination Targeted Therapy and Radiotherapy
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