- Email: [email protected]
In Regard to Brown and Adler
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
COMMENTS Innovation in Radiation Oncology In Regard to Brown and Adler To the Editor: Drs Brown and Adler hypothesize that radiation oncology equipment development is stifling innovation by focusing on the development of stereotactic body radiation therapy (SBRT) and not radiation biologyebased treatment modifiers (1). Their proposed solution is to have equipment manufacturers sponsor clinical trials with radiation sensitizersda “holistic ‘full service’ approach to cancer therapy”dbecause drug companies and cooperative groups are not interested in funding such research. As a radiation oncologist who has held senior positions in pharmaceutical and biotechnology companies, such a perspective is shortsighted, neglecting the clinical benefits of stereotactic body radiation therapy and other technologic advances, and suggesting that equipment manufacturers will invest in opportunities from which they will see little return. Most industry-sponsored drug research does not involve radiation because, with rare exceptions (eg, cetuximab [2], temozolomide [3]), there is not a clear pathway to marketing approval and a subsequent return on investment. Reimbursement, however, may be secured for medications included in clinical guidelines, such as those published by the National Comprehensive Cancer Network. To best collaborate with the pharmaceutical/biotechnology industry, radiation oncologists need to think more broadly than simply radiation sensitization or protection. Opportunities include, but are not limited to, the following: (1) Identifying populations, by molecular or other biomarkers, most likely to benefit from the combination of radiation with a specific drug; (2) Using SBRT to control limited metastatic disease in patients whose disease is otherwise controlled with systemic agents, as has been described for non-small cell lung cancer (4); such a strategy can extend the use of effective targeted therapies; (3) Combining immunotherapeutic agents with radiation. As described for melanoma, radiation may act as a noninvasive tumor vaccine (5). Similar effects may be observed in other solid tumors and hematologic malignancies; for example, a small dose of radiation combined with immune checkpoint inhibition may be effective in patients with Hodgkin lymphoma, abrogating the need for intensive
Int J Radiation Oncol Biol Phys, Vol. 93, No. 4, pp. 934e942, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved.
chemotherapy (6); and (4) Developing systemically administered, unsealed radiopharmaceuticals. Radium-223 for patients with bone metastases is now approved and other a-particle emitters are currently in development. For these agents to be clinically and commercially successful, radiation oncologists must be their champions. Pharmaceutical companies may fund such research through investigator grants, or as industry-sponsored trials for truly promising therapies. Other sources, including but not limited to disease-specific foundations, may also provide support. Last, academic researchers, both physicians and biologists, can consider a sabbatical working for a pharmaceutical or biotechnology company. Such experience will allow practitioners to learn how decisions are made, timelines defined, and resources (both human and financial) allocated to develop oncology drugs. Marc S. Rudoltz, MD MSR Healthcare Consultants LLC West Orange, New Jersey Rutgers - Robert Wood Johnson Medical School New Brunswick, New Jersey http://dx.doi.org/10.1016/j.ijrobp.2015.08.018
References 1. Brown JM, Adler JR Jr. Is equipment development stifling innovation in radiation oncology? Int J Radiat Oncol Biol Phys 2015;92: 713-714. 2. 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 cetuximabinduced rash and survival. Lancet Oncol 2010;11:21-28. 3. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10: 459-466. 4. Weickhardt AJ, Scheier B, Malachy Burke J, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small cell lung cancer. J Thorac Oncol 2012;7:1807-1814. 5. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 2012; 366:925-931.
Volume 93 Number 4 2015 6. Moskowitz CH, Ribrag V, Michot JM, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: Preliminary results from a phase 1b study (Abstr.). Blood 2014;124:290.
In Regard to Brown and Adler To the Editor: Brown and Adler (1) argue that exciting opportunities exist in combining stereotactic body radiation therapy (SBRT) with biologically based agents, but that the radiation therapy device industry may be impeding progress in this area by focusing primarily on technological development. Although we respect their viewpoint, we feel obliged to clarify the position of the companies named in the commentary (Accuray, Elekta, and Varian Medical Systems). We agree that technologies used to deliver SBRT have altered the landscape of radiation oncology and could enhance the effects of agents such as radiosensitizers and immunotherapeutics. However, it is noteworthy that the focus industry has placed on technological development has made novel applications of these biologics possible in the first place. This very reasoning stands as proof that equipment development is not stifling innovation, but instead enabling it. Our industry is distinct from the biotechnology industry in that each company’s respective product roadmap is largely driven by our customers. Consequently, many innovations are a direct result of collaborative research with these customers. Our companies do, in fact, invest many millions of dollars per year in these activities. Although our technology research and development (R&D) budgets may be lower than those in the biotechnology industry, it could be argued that the effectiveness of radiation therapy relative to this investment constitutes justification for the value proposition for our specialty. In addition, each of our companies have Medical Affairs departments that collaborate extensively with customers, pursuing innovations that improve clinical practice. A key challenge has been to decide, among the scope of innovations, which ones will yield the most benefit. The authors have cited at least 7 examples of arguably nascent, mammoth, and expensive (2) biotechnology initiatives, likely accompanied by hundreds of research questions to be addressed during preclinical phases. Given the stage and breadth of these initiatives, it is nearly impossible for us to know where we would focus. To best serve our community and steer our investments, further direction would be required that is not currently available. The authors also suggest establishing a mechanism to “singly or jointly set up funds” to test these approaches. Although this might seem appealing, the proposed areas are often misaligned with the core businesses of our companies. Exploration of biologics has typically been reserved for pharmaceutical organizations with appropriate resources, competence, and product development infrastructures. Impactful investment made into this space not only risks
Comments
935
affecting our companies’ ability to support R&D that more directly improves radiation therapy systems, but also has product cost implications that could further impede access to these lifesaving technologies. Brown and Adler also predict that upcoming technology innovation and associated improvements in clinical outcomes may be minimal compared with those over the past 20 years. In our capacities, we are seeing absolutely no evidence of this, a view shared by many renowned colleagues in our field (3). In summary, we strongly believe industry’s current focus on technology development does not undermine significant clinical advances in radiation oncology. Our companies will continue to focus on technology R&D, with the aim of making it easier, safer, and more efficient to deliver SBRT and other advanced treatments to patients worldwide, while continuing to selectively explore and support nonhardware research that is ongoing. We believe this approach will distinguish radiation oncology as a prominent specialty and not, as the authors suggest, marginalize it. Joel Goldwein, MD Elekta Sunnyvale, California Fabienne Hirigoyenberry Lanson, PhD Accuray Sunnyvale, California Deepak Khuntia, MD Varian Medical Systems Palo Alto, California http://dx.doi.org/10.1016/j.ijrobp.2015.08.017
References 1. Brown JM, Adler JR Jr. Is equipment development stifling innovation in radiation oncology? Int J Radiat Oncol Biol Phys 2015;92:713-714. 2. Morgan S, Grootendorst P, Lexchin J, et al. The cost of drug development: A systematic review. Health Policy 2011;100:4-17. 3. Chetty IJ, Martel MK, Jaffray DA, et al. Technology for innovation in radiation oncology. Int J Radiat Oncol Biol Phys 2015;93:485-492.
In Reply to Rudoltz and Goldwein et al To the Editor: We appreciate the responses to our Commentary (1-3) and are delighted that it has stimulated this debate. Given our mutual interests in advancing the efficacy and promoting the field of radiation oncology, we believe this discussion is healthy. First, to clarify our position, which may have been misunderstood, we do not wish to “neglect the clinical benefits of SBRT and other technological advances.” Quite the contrary: we agree that the technological advances made in the past 20 years have revolutionized radiation therapy via stereotactic radiosurgery and stereotactic body radiation therapy (SBRT) and
Radiation Oncology biology
physics
www.redjournal.org
COMMENTS Innovation in Radiation Oncology In Regard to Brown and Adler To the Editor: Drs Brown and Adler hypothesize that radiation oncology equipment development is stifling innovation by focusing on the development of stereotactic body radiation therapy (SBRT) and not radiation biologyebased treatment modifiers (1). Their proposed solution is to have equipment manufacturers sponsor clinical trials with radiation sensitizersda “holistic ‘full service’ approach to cancer therapy”dbecause drug companies and cooperative groups are not interested in funding such research. As a radiation oncologist who has held senior positions in pharmaceutical and biotechnology companies, such a perspective is shortsighted, neglecting the clinical benefits of stereotactic body radiation therapy and other technologic advances, and suggesting that equipment manufacturers will invest in opportunities from which they will see little return. Most industry-sponsored drug research does not involve radiation because, with rare exceptions (eg, cetuximab [2], temozolomide [3]), there is not a clear pathway to marketing approval and a subsequent return on investment. Reimbursement, however, may be secured for medications included in clinical guidelines, such as those published by the National Comprehensive Cancer Network. To best collaborate with the pharmaceutical/biotechnology industry, radiation oncologists need to think more broadly than simply radiation sensitization or protection. Opportunities include, but are not limited to, the following: (1) Identifying populations, by molecular or other biomarkers, most likely to benefit from the combination of radiation with a specific drug; (2) Using SBRT to control limited metastatic disease in patients whose disease is otherwise controlled with systemic agents, as has been described for non-small cell lung cancer (4); such a strategy can extend the use of effective targeted therapies; (3) Combining immunotherapeutic agents with radiation. As described for melanoma, radiation may act as a noninvasive tumor vaccine (5). Similar effects may be observed in other solid tumors and hematologic malignancies; for example, a small dose of radiation combined with immune checkpoint inhibition may be effective in patients with Hodgkin lymphoma, abrogating the need for intensive
Int J Radiation Oncol Biol Phys, Vol. 93, No. 4, pp. 934e942, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved.
chemotherapy (6); and (4) Developing systemically administered, unsealed radiopharmaceuticals. Radium-223 for patients with bone metastases is now approved and other a-particle emitters are currently in development. For these agents to be clinically and commercially successful, radiation oncologists must be their champions. Pharmaceutical companies may fund such research through investigator grants, or as industry-sponsored trials for truly promising therapies. Other sources, including but not limited to disease-specific foundations, may also provide support. Last, academic researchers, both physicians and biologists, can consider a sabbatical working for a pharmaceutical or biotechnology company. Such experience will allow practitioners to learn how decisions are made, timelines defined, and resources (both human and financial) allocated to develop oncology drugs. Marc S. Rudoltz, MD MSR Healthcare Consultants LLC West Orange, New Jersey Rutgers - Robert Wood Johnson Medical School New Brunswick, New Jersey http://dx.doi.org/10.1016/j.ijrobp.2015.08.018
References 1. Brown JM, Adler JR Jr. Is equipment development stifling innovation in radiation oncology? Int J Radiat Oncol Biol Phys 2015;92: 713-714. 2. 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 cetuximabinduced rash and survival. Lancet Oncol 2010;11:21-28. 3. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10: 459-466. 4. Weickhardt AJ, Scheier B, Malachy Burke J, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small cell lung cancer. J Thorac Oncol 2012;7:1807-1814. 5. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 2012; 366:925-931.
Volume 93 Number 4 2015 6. Moskowitz CH, Ribrag V, Michot JM, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: Preliminary results from a phase 1b study (Abstr.). Blood 2014;124:290.
In Regard to Brown and Adler To the Editor: Brown and Adler (1) argue that exciting opportunities exist in combining stereotactic body radiation therapy (SBRT) with biologically based agents, but that the radiation therapy device industry may be impeding progress in this area by focusing primarily on technological development. Although we respect their viewpoint, we feel obliged to clarify the position of the companies named in the commentary (Accuray, Elekta, and Varian Medical Systems). We agree that technologies used to deliver SBRT have altered the landscape of radiation oncology and could enhance the effects of agents such as radiosensitizers and immunotherapeutics. However, it is noteworthy that the focus industry has placed on technological development has made novel applications of these biologics possible in the first place. This very reasoning stands as proof that equipment development is not stifling innovation, but instead enabling it. Our industry is distinct from the biotechnology industry in that each company’s respective product roadmap is largely driven by our customers. Consequently, many innovations are a direct result of collaborative research with these customers. Our companies do, in fact, invest many millions of dollars per year in these activities. Although our technology research and development (R&D) budgets may be lower than those in the biotechnology industry, it could be argued that the effectiveness of radiation therapy relative to this investment constitutes justification for the value proposition for our specialty. In addition, each of our companies have Medical Affairs departments that collaborate extensively with customers, pursuing innovations that improve clinical practice. A key challenge has been to decide, among the scope of innovations, which ones will yield the most benefit. The authors have cited at least 7 examples of arguably nascent, mammoth, and expensive (2) biotechnology initiatives, likely accompanied by hundreds of research questions to be addressed during preclinical phases. Given the stage and breadth of these initiatives, it is nearly impossible for us to know where we would focus. To best serve our community and steer our investments, further direction would be required that is not currently available. The authors also suggest establishing a mechanism to “singly or jointly set up funds” to test these approaches. Although this might seem appealing, the proposed areas are often misaligned with the core businesses of our companies. Exploration of biologics has typically been reserved for pharmaceutical organizations with appropriate resources, competence, and product development infrastructures. Impactful investment made into this space not only risks
Comments
935
affecting our companies’ ability to support R&D that more directly improves radiation therapy systems, but also has product cost implications that could further impede access to these lifesaving technologies. Brown and Adler also predict that upcoming technology innovation and associated improvements in clinical outcomes may be minimal compared with those over the past 20 years. In our capacities, we are seeing absolutely no evidence of this, a view shared by many renowned colleagues in our field (3). In summary, we strongly believe industry’s current focus on technology development does not undermine significant clinical advances in radiation oncology. Our companies will continue to focus on technology R&D, with the aim of making it easier, safer, and more efficient to deliver SBRT and other advanced treatments to patients worldwide, while continuing to selectively explore and support nonhardware research that is ongoing. We believe this approach will distinguish radiation oncology as a prominent specialty and not, as the authors suggest, marginalize it. Joel Goldwein, MD Elekta Sunnyvale, California Fabienne Hirigoyenberry Lanson, PhD Accuray Sunnyvale, California Deepak Khuntia, MD Varian Medical Systems Palo Alto, California http://dx.doi.org/10.1016/j.ijrobp.2015.08.017
References 1. Brown JM, Adler JR Jr. Is equipment development stifling innovation in radiation oncology? Int J Radiat Oncol Biol Phys 2015;92:713-714. 2. Morgan S, Grootendorst P, Lexchin J, et al. The cost of drug development: A systematic review. Health Policy 2011;100:4-17. 3. Chetty IJ, Martel MK, Jaffray DA, et al. Technology for innovation in radiation oncology. Int J Radiat Oncol Biol Phys 2015;93:485-492.
In Reply to Rudoltz and Goldwein et al To the Editor: We appreciate the responses to our Commentary (1-3) and are delighted that it has stimulated this debate. Given our mutual interests in advancing the efficacy and promoting the field of radiation oncology, we believe this discussion is healthy. First, to clarify our position, which may have been misunderstood, we do not wish to “neglect the clinical benefits of SBRT and other technological advances.” Quite the contrary: we agree that the technological advances made in the past 20 years have revolutionized radiation therapy via stereotactic radiosurgery and stereotactic body radiation therapy (SBRT) and