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Where is clinical research for radiotherapy going? Cross-sectional comparison of past and contemporary phase III clinical trials

Where is clinical research for radiotherapy going? Cross-sectional comparison of past and... Purpose: The features of past and contemporary phase III clinical trials for radiotherapy were reviewed to activate future clinical trials and to advise on actual clinical practice. Methods and materials: The phase III clinical trials for radiotherapy were searched in the database of ‘ClinicalTrials. gov’ by the U.S. National Institute of Health. Using the staring date, the studies during each period of 4 years were collected for the past (from Jan 2000 to Dec 2003) and contemporary (July 2014 to June 2018) years. For the investigated subjects, the patterns of studies were classified as: Category A, the comparisons of rival radiotherapy protocols; Category B, the comparisons of multidisciplinary approaches; Category C, the investigation of supplementary agents; and Category D, the investigation of optimal partners for concurrent radiotherapy. Results: The number of studies increased, from 96 past to 158 contemporary studies. The patterns of studies were similar with the mild increase of Category A in the contemporary years (22.9% vs. 29.1%). For the study locations and the funding sources, the Chinese studies (2.1% vs. 34.2%, P < 0.001) and the affiliated institutions of researchers (37.5% vs. 72.2%, P < 0.001) markedly increased in the contemporary years from the past Western studies and non- profit organization, respectively. The robust radiation techniques were more usual in the contemporary years (11.5% vs. 44.9%, P < 0.001). The fractionation schedule and delivery technique were the common issues in both past and contemporary years of Category A. In Category B, the indications of stereotactic radiotherapy was the rising concern, with eight ongoing studies. Except for the studies of palliative or prophylactic goals and stereotactic radiotherapy, the escape from conventional fraction size was 37.9% (36/95) in the contemporary years with the median fraction size of 2.5 Gy (range 2.05–6.6 Gy) in the comparison with 19.0% (15/79) in the past years (P = 0.006). Conclusions: To activate the clinical trials for radiotherapy, the funding sources would be diversified, including industrial support. Hypofractionated schedules using robust techniques could be preemptively considered in actual clinical practice. Keywords: Radiotherapy, Clinical trials, Hypofraction, Stereotactic radiotherapy Introduction accelerators [1]. Currently, the radiotherapy usage rates Radiotherapy has had a long-term history of over a hun- as the first course of treatment reached about 31% in US dred years of treating malignant cancer after X-rays and 2014 statistics [2]. However, for better clinical outcomes radium were discovered at the end of the nineteenth through qualified radiotherapy, a radiation oncologist century. Initially, radium and low-energy machines were must understand the place of radiotherapy and cooper- used for the easily accessible tumors and radiotherapy ate with the surgical and medical oncologists in this era began to expand the field to all malignant cancers of multidisciplinary approaches. thanks to the generalization of mega-voltage linear Clinical trials systematize the usefulness of individual clinical experience and distinguish the values of specific treatments. The well-designed randomized controlled * Correspondence: irionyws@korea.ac.kr clinical trials can establish the evidence-based medicine Radiation Oncology, Ansan Hospital, Korea University, 123 Jeokgeum-ro, Danwon-gu, Ansan, Gyeonggi-do 15355, Republic of Korea © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Park et al. Radiation Oncology (2020) 15:36 Page 2 of 7 to guide the standard management and to suggest future Category C: The studies to investigate supplementary strategies. Actually, the phase III clinical trials which agents (management) to support the therapeutic were completed before a decade would construct the effectiveness and tolerability of radiotherapy, and present clinical guideline in consideration of the mature Category D: The studies to investigate optimal partners period. In addition, through the overview of the recent of pharmaceutical agents or procedures with clinical trials, the emerging issues could be well identi- radiotherapy. fied. For optimal radiotherapy, there is no better method than to look back at the implemented and implementing The information on protocol number, study status, clinical trials with radiotherapy. disease conditions, radiotherapy aim, the endpoints, Hence, we reviewed the features of phase III clinical sponsor/collaborators, study location, and the details of trials in the past and contemporary radiotherapy. Conse- radiotherapy, surgery, and pharmaceutical agents was quently, the radiation oncologists could figure out the collected from the web page of “ClinicalTrials”. If the de- context of change and existing problems, and get advice tails of treatments for each study were insufficient, the on actual clinical practice and future clinical trials. In open information was collected from the web sites addition, the directions to further activate clinical re- “Pubmed” and “Google” using protocol number and searches could be discussed in radiation oncology. other ID of trials. The main end-points of this study were (1) to measure the volume of clinical trials regarding radiotherapy, (2) Methods to observe the changes of funding sources and study lo- For searching for information on clinical trials, we used cations, (3) to consider the change of radiation schedule the database of ‘ClinicalTrials.gov’ by the U.S. National and fraction size, and (4) to check the application of the Institute of Health. The clinical trials of phase III includ- state-of-the-art techniques. A Chi-square test was con- ing the term “Radiotherapy” were searched for in terms ducted to compare the difference of the past and con- of all study statuses (recruiting/ enrolling by invitation/ temporary years. A two-sided p < 0.05 was considered active, not recruiting/ suspended/ terminated/ com- significant. SPSS 20.0 (IBM SPSS, Inc., Chicago, IL) was pleted/ withdrawn/ unknown status) except for the sta- used for the analysis. tus of “not yet recruiting”. The starting date of the study was limited from Jan 2000 to Dec 2003 and from July Results 2014 to June 2018. The eligible criteria were studies in Of the total of 206 past and 351 contemporary studies, 96 which (1) radiotherapy had an obvious role for the and 158 studies satisfied our eligibility criteria for our therapeutic outcomes, (2) radiotherapy was done for a studies, respectively. (Figure 1) The number of phase III malignant cancer including borderline malignancies, and clinical trials regarding radiotherapy increased by 64.6% in (3) external beam radiotherapy was applied in any arm. the contemporary years. While Category A increased by The exclusion criteria were studies in which (1) the sub- 6.2% in the contemporary years in comparison with the ject was hematologic or lymphatic malignancies or only past years, however, the difference was not remarkable children, (2) the stratification was done after performing (P = 0.309). One and three studies in the past and contem- radiotherapy, (3) the effectiveness of neoadjuvant or con- porary years had to be included in both categories, be- solidative management that did not involve radiotherapy cause they were designed by the 2 X 2 fractions model, was investigated without the change of radiotherapy protocol in all allocated arms, and (4) the details of hor- monal therapy, such as drug combination, duration and timing, were investigated in breast and prostate cancer. First, to know the patterns during each period of 4 years, the past years (Jan 2000 to Dec 2003) and the con- temporary years (July 2014 to June 2018) studies were divided according to the start date of the study. Second, the studies were classified with four categories in terms of the investigating subjects as below. Category A: The studies to compare rival radiotherapy protocols, (e.g. treatment schedule, radiation field, or techniques), Fig. 1 Flow of selection process from all phase III studies with the Category B: The studies to compare the standard keyword “radiotherapy” to eligible studies therapy and new ones in multidisciplinary approaches, Park et al. Radiation Oncology (2020) 15:36 Page 3 of 7 and all four studies were associated with category A. The After excluding the studies with palliative or prophy- primary radiotherapy was intended to cure the actual tu- lactic aims and applying SBRTs, 79 and 95 studies of the mors in 58.3 and 63.9% of the past and contemporary past and contemporary years, respectively, addressed studies, respectively (P = 0.299). The studies administering their fraction schedule of radiotherapy in protocols. The concurrent chemotherapy were used in the past years of escape from conventional daily fraction size of 1.8–2Gy 54.1% and contemporary years of 63.3% (P =0.350). was 19.0% (15/79, 5 hyperfraction regimen) in the past Whereas the past studies was done in Western areas and years and 37.9% (36/95, 1 hyperfraction regimen) in the supported by non-profit organizations, the studies from contemporary years (P = 0.006). In terms of CCRT China and affiliated institutions of the researcher mark- protocol, 14.6% (7/48, 5 hyperfraction regimen) and edly increased in the contemporary years (both P <0.001). 27.3% (21/77, 1 hyperfraction regimen) of studies used a The weak industrial supports were unchanged in the past daily fraction size higher than 2 Gy in the past and con- (7.3%) and contemporary (8.9%) years. For the endpoints, temporary years, respectively (P = 0.098). The median the toxicity was more commonly observed in contempor- fraction size of hypofraction was 2.5 Gy (range 2.05–6.6 ary years (P =0.003) (Table 1). Gy) and 2.3 Gy (range 2.12–5.0 Gy) in whole and CCRT The contemporary studies in Category A were con- studies in the contemporary years, respectively (Fig. 3). cerned with the fractionation schedule in 43.5% (20/46) of cases without the significant change of detailed pat- Discussion terns. (Fig. 2) The applications of hypofraction schedules Although the phase III studies concerning radiotherapy was expanded from rectal and prostate cancers of the were abundantly registered, their increasing rates were not past years to breast, lung, esophagus, and head and neck surprising in comparison with the growth rates of all fields of the contemporary years, and the median fraction size concerning cancer. In the same periods of the past and of the experimental group was 2.66 Gy (range 2.05–5 contemporary years, the registered phase III clinical trials Gy) if one stereotactic body radiotherapy (SBRT) was ex- to be searched for with the keyword of “cancer” doubled, cluded. However, it was not observed to use hyperfrac- from 827 studies to 1674 studies on the database of ‘Clini- tion schedules in the contemporary years. Meanwhile, calTrials.gov’. Of course, that is related to the growing the dose escalation of prostate cancer was investigated market for pharmaceutical agents in malignancy treat- in the past years; the dose de-escalation of human papil- ment, and the industrial sponsors strongly supported ap- lomavirus (HPV) positive head and neck cancer was ex- proximately a third (286/827) of the studies in past years amined in contemporary years. The studies regarding and half of the studies (757/1674) in the contemporary dose prescription advised by positron emission tomog- years. On previous report to analyze oncologic trials re- raphy (PET) were noticeable in lung, head and neck and gardless of the phases of study during recent 10 years, the cervical cancer (Supplementary 1). radiotherapy trials consisted of only 5.3% of whole trials Of the category B, to decide the optimal strategies of and received a week industrial support of 5.8% [3]. multidisciplinary approaches, a few changes were found. How can the studies about radiotherapy be more ac- In the past years, the main concerns were concurrent tively performed? The phase III studies of 2 X 2 frac- chemoradiotherapy (CCRT) vs. radiotherapy or chemo- tional stratification, we guess, could be a good model. therapy alone (13 studies) and additional consolidation For example, RTOG 0617 studies examined total radi- therapy after radiotherapy (7 studies). Currently, the ris- ation dose and usefulness of cetuximab in advanced- ing concerns were additional radiotherapy using SBRT stage lung cancer [4], and four studies in our review, (8 studies) in oligometastases, brain metastases, and he- including NCT00024349 (CRC-BC2001) for bladder can- patocellular carcinoma, and the comparison of adjuvant cer, applied this stratification [5, 6]. Of course, these vs. neoadjuvant therapies (6 studies) in soft tissues, kinds of protocols need more eligible numbers to inhibit stomach, rectal, and penile cancer. the under-power of statistics and thus, they need more For category C, the radio-sensitizers, general tolerability time and cooperation between physicians to publish the or pain and specific toxicity were equally examined in the final outcomes, in addition to the effort to make well- past years. The contemporary concerns were intensified in designed protocols. However, it is more economical to the areas of acute toxicity, such as mucositis, skin reaction reduce the duplicated labors and costs of clinical trials if and urinary symptom. For Category D, new pharmaceut- the eligible condition to investigate is similar. From this ical agents were actively reflected in the contemporary viewpoint, the communication of radiation oncologists years. Whereas most studies were on the traditional and other oncologists could be necessary to clarify the chemo-agents (77.8%, 14/18) in the past years, the studies specific details for radiotherapy and multidisciplinary administering targeted agents, immunotherapy and antivi- management earlier. The industrial funds to plan new rals (41.4%, 12/29) caught up much of the chemo-agents pharmaceutical agents could also be indirectly used for in contemporary years (Table 2). radiotherapy. Park et al. Radiation Oncology (2020) 15:36 Page 4 of 7 Table 1 Studies’ characteristics in the past and contemporary years Past years (Jan 2000 – Dec 2004, N = 96) Contemporary years (July 2014 – June 2018, N = 158) P value Category A 22 (22.9%) 46 (29.1%) 0.309 B 39 (40.6%) 64 (40.5%) 0.807 C 18 (18.8%) 22 (13.9%) 0.306 D 18 (18.8%) 29 (18.4%) 0.937 Aim of radiotherapy Adjuvant 27 43 0.875 Definite 56 82 0.299 Neoadjuvant 11 19 0.892 Palliative 7 21 0.139 Prophylactic 2 4 Any 1 1 Disease status Non-: Metastatic: Any 86: 6: 4 133: 23: 2 0.065** Naïve: Recurrent: Any 88: 1: 7 135: 2: 21 1.000** Sponsors/Collaborators Non-Profitable organization 67 47 < 0.001 Industry 8 14 0.885 Institution of researcher 36 114 < 0.001 Locations < 0.001 Western: China: World-wide: Others 82: 2: 5: 7 76: 54: 10: 18 Participant Institutions 0.770 Single: Multiple 27: 69 41: 117 Concurrent administration of drugs 0.350** Yes: No: Not specified 53: 40: 3 100: 58: 0 Robust delivery technique 11 71 < 0.001 SBRT 3 22 IMRT 8 48 Proton 0 3 Endpoints Survival 76 129 0.627 Tumor response 33 33 0.017 Toxicity 52 114 0.003 Quality of life 40 70 0.681 duplicated with other sub-items **Chi-square tests were conducted excluding “any” or “non-specified” items Category A: to compare rival radiotherapy protocols, B: to compare the strategies in multidisciplinary approaches, C: to investigate supplementary agents for radiotherapy and D: to investigate optimal partners with radiotherapy Western area included USA, Canada, European countries, Australia and New Zealand SBRT Stereotactic body radiotherapy, IMRT Intensity modulated radiotherapy The expansion of clinical trials to non-Western countries National Clinical Trials Network could insure the quality of could be welcome. It can increase the number of studies studies for radiotherapy through the structure name librar- and give more clinical information for the more frequently iesand software toolsand templatesinthe US [7]. developed malignancies in non-Western countries. How- Thanks to intensity modulated radiotherapy (IMRT) tech- ever, to insure the quality of studies, it is necessary to trans- niques and the concept of simultaneous integrated boost to fer the know-how and settle for an efficient system in these intensify the radiation dose on the restricted local area, a emerging locations. It is a typical model that the alliance of hypofractionated schedule would be the inevitable trend for Park et al. Radiation Oncology (2020) 15:36 Page 5 of 7 Fig. 2 The number of studies that compared rival radiotherapy protocols doubled, from 22 in past years to 46 in contemporary years. The two main issues were fraction size and radiation technique in both the past and contemporary years radiotherapy, making it more comfortable for patients by re- favored the SBRT over open surgery in brain metastases ducing the treatment period while showing equivalent clin- and lobectomy in early lung cancer [10, 11]. The clinical ical outcomes. It is notable that the median 2.5 Gy was outcomes were prospective in a phase I/II trial of hepatocel- applied in approximately one third of the contemporary tri- lular carcinoma [12] and an initial trial of oligometastases in als. The SBRT technique broadened its areas from brain prostate cancer [13], and the relevant studies using SBRT metastases to early-stage lung cancer, oligometastases, and could be continued. Additionally, the prescription guidance hepatocellular carcinoma. Through the robust advance of by PET is interesting for achieving a personalized hypofrac- linear accelerators [8], liniac-based stereotactic radiosurgery tion schedule. It was feasible in the initial reports of head rapidly disseminated in brain metastases in the US [9]. and neck cancer, non-small-cell lung cancer, and esophageal There were a few reports about cost effectiveness that cancer [14–17]. Table 2 Investigations’ characteristics in category C and D Past years (Jan 2000 – Dec 2004) Contemporary years (July 2014 – June 2018) P value Category C 0.364 Sensitizer 6 4 General tolerability or Pain 6 6 Specific toxicity 6 12 - Skin reaction - 1 - 4 - Oral mucositis - 3 - 7 - Xerostomia - 2 - 0 - Urinary symptom - 0 - 1 Category D 0.002 Cytotoxic drug 14 17 New drug 2 12 - Targeted agent - 2 - 8 - Immunotherapy - 0 - 3 - Antivirals - 0 - 1 Surgery 2 0 Park et al. Radiation Oncology (2020) 15:36 Page 6 of 7 Fig. 3 Studies using hyper- or hypo-fractional radiotherapy. Hyperfraction schedules for lung, head and neck, and bladder cancer were tried in past years (left panel), but the interests decreased in contemporary year (right panel). Hypofraction schedules were newly tried for breast and hepatobiliary cancer in contemporary years. * The studies applying a hyperfraction schedule were indicated below the line of 2.0 Gy The phase III clinical trials were designed on the basis because of the bulk loading to review all clinical trials of the positive outcomes of early phase studies or credible from 2000 to 2018. Therefore, it would be sufficient to observations. If the progress of experimental investigations see the landscape of clinical trials regarding radiotherapy is active both in quality and in quantity, there would be and prepare for future studies. some portions to preemptively consider those practice case by case. Surely, other experts suggested that the cost- Conclusion effectiveness of new strategy preferentially is assessed [18]. The number of clinical trials consistently increased in We thought that the above mentioned trends of hypofrac- non-Western area, especially. To more activate the clin- tion schedule using IMRT, SBRT and the collaboration ical trials for radiotherapy, it is necessary that the fund- with novel image technologies could be major candidates. ing sources should be diversified, including industrial The therapeutic ratio for late toxicity could be an in- support. Hypofractionated schedules using robust tech- teresting viewpoint in the comparison of the past and niques which were investigated in the contemporary contemporary studies. Meanwhile, the radiation protec- years could be preemptively considered in actual clinical tors of amifostine and supplementary agents of salagen practice for various kinds of cancer. Radiation oncolo- used for reducing late toxicity, such as xerostomia, the gists have to understand the trends of clinical trials for hippocampal-sparing brain radiotherapy using the IMRT radiotherapy and try the next well-designed clinical tri- technique [19], and the dose de-escalation in HPV pa- als. Keeping in mind the place of radiotherapy in multi- tients using biomarkers [20], were actively tried in the disciplinary approaches overall, the cooperation with contemporary years. The supplementary agents focused medical and surgical oncologists would effectively pro- on acute and subacute toxicity of oral mucosa and skin. mote better clinical trials and establish the evidence for One may also wonder whether the synergistic effects of radiotherapy sooner. the combination of radiotherapy and immunotherapy could replace the cytotoxic chemotherapy [21]. Supplementary information There were a few limitations of this review. First, re- Supplementary information accompanies this paper at https://doi.org/10. searchers reported on their studies freely on the plat- 1186/s13014-020-01489-4. form of “ClinicalTrials.gov” and the records were largely Additional file 1: Supplementary 1. The details of investigations in faithful. However, there was some missing information category A (comparison of rival radiotherapy protocols). we wanted to collect, especially in the past years. Sec- ond, there was a possibility that we missed studies, be- Abbreviations cause we used only the platform of “clinical trial,” CCRT: Concurrent Chemoradiotherapy; HPV: Human Papillomavirus; although it is the best known one in the world. Last, we IMRT: Intensity Modulated Radiotherapy; PET: Positron Emission Tomography; observed the studies by the cross-sectional method SBRT: Stereotactic Body Radiotherapy Park et al. Radiation Oncology (2020) 15:36 Page 7 of 7 Acknowledgements 14. Berwouts D, Olteanu LA, Duprez F, Vercauteren T, De Gersem W, De Neve Not applicable. W, et al. Three-phase adaptive dose-painting-by-numbers for head-and-neck cancer: initial results of the phase I clinical trial. Radiother Oncol. 2013; 107(3):310–6. Authors’ contributions 15. Hoffmann L, Knap MM, Khalil AA, Lutz CM, Sloth MD. The NARLAL2 dose WSY designed the overall study with contributions from SP. SP and CHR escalation trial: dosimetric implications of inter-fractional changes in organs collected and analyzed data. All authors wrote and finally approved this at risk. Acta Oncol. 2018;57(4):473–9. manuscripts. 16. Kong FM, Ten Haken RK, Schipper M, Frey KA, Hayman J, Gross M, et al. Effect of Midtreatment PET/CT-adapted radiation therapy with concurrent Funding chemotherapy in patients with locally advanced non-small-cell lung Cancer: This work was supported by Korea University [grant numbers K1912721]. a phase 2 clinical trial. JAMA Oncol. 2017;3(10):1358–65. 17. Yap ML, Sun A, Higgins J, Clarke K, Marshall A, Becker N, et al. Adaptive Availability of data and materials dose escalation using serial four-dimensional positron emission The data that support the findings of this study are available in http://www. tomography/computed tomography scans during radiotherapy for locally ClinicalTrials.gov. advanced non-small cell lung Cancer. Clin Oncol. 2016;28(12):e199–205. 18. van Loon J, Grutters J, Macbeth F. Evaluation of novel radiotherapy Ethics approval and consent to participate technologies: what evidence is needed to assess their clinical and cost Not applicable. effectiveness, and how should we get it? Lancet Oncol. 2012;13(4):e169–77. 19. Zhao R, Kong W, Shang J, Zhe H, Wang YY. Hippocampal-sparing whole- Consent for publication brain radiotherapy for lung Cancer. Clin Lung Cancer. 2017;18(2):127–31. Not applicable. 20. Chen AM, Felix C, Wang PC, Hsu S, Basehart V, Garst J, et al. Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma Competing interests of the oropharynx: a single-arm, phase 2 study. Lancet Oncol. 2017;18(6): The authors declare that they have no competing interests. 803–11. 21. Illidge T. Turning radiotherapy into an effective systemic anti-cancer Received: 20 November 2019 Accepted: 10 February 2020 treatment in combination with immunotherapy. Clin Oncol. 2015;27(12): 696–9. References 1. Connell PP, Hellman S. Advances in radiotherapy and implications for the Publisher’sNote next century: a historical perspective. Cancer Res. 2009;69(2):383–92. Springer Nature remains neutral with regard to jurisdictional claims in 2. Royce TJ, Qureshi MM, Truong MT. Radiotherapy utilization and published maps and institutional affiliations. fractionation patterns during the first course of Cancer treatment in the United States from 2004 to 2014. J Am Coll Radiol. 2018;15(11):1558–64. 3. Liu X, Zhang Y, Tang LL, Le QT, Chua MLK, Wee JTS, et al. Characteristics of radiotherapy trials compared with other oncological clinical trials in the past 10 years. JAMA Oncol. 2018;4(8):1073–9. 4. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2): 187–99. 5. Huddart RA, Hall E, Hussain SA, Jenkins P, Rawlings C, Tremlett J, et al. Randomized noninferiority trial of reduced high-dose volume versus standard volume radiation therapy for muscle-invasive bladder cancer: results of the BC2001 trial (CRUK/01/004). Int J Radiat Oncol Biol Phys. 2013; 87(2):261–9. 6. James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, et al. 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Comparing the cost-effectiveness of two brain metastasis treatment modalities from a payer's perspective: stereotactic radiosurgery versus surgical resection. Clin Neurol Neurosurg. 2013;115(3):276–84. 12. Bujold A, Massey CA, Kim JJ, Brierley J, Cho C, Wong RK, et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol. 2013;31(13):1631–9. 13. Siva S, Bressel M, Murphy DG, Shaw M, Chander S, Violet J, et al. Stereotactic Abative body radiotherapy (SABR) for Oligometastatic prostate Cancer: a prospective clinical trial. Eur Urol. 2018;74(4):455–62. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Where is clinical research for radiotherapy going? Cross-sectional comparison of past and contemporary phase III clinical trials

Park, Sunmin; Rim, Chai Hong; Yoon, Won Sup
Radiation Oncology , Volume 15 (1) – Feb 14, 2020
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Abstract

Purpose: The features of past and contemporary phase III clinical trials for radiotherapy were reviewed to activate future clinical trials and to advise on actual clinical practice. Methods and materials: The phase III clinical trials for radiotherapy were searched in the database of ‘ClinicalTrials. gov’ by the U.S. National Institute of Health. Using the staring date, the studies during each period of 4 years were collected for the past (from Jan 2000 to Dec 2003) and contemporary (July 2014 to June 2018) years. For the investigated subjects, the patterns of studies were classified as: Category A, the comparisons of rival radiotherapy protocols; Category B, the comparisons of multidisciplinary approaches; Category C, the investigation of supplementary agents; and Category D, the investigation of optimal partners for concurrent radiotherapy. Results: The number of studies increased, from 96 past to 158 contemporary studies. The patterns of studies were similar with the mild increase of Category A in the contemporary years (22.9% vs. 29.1%). For the study locations and the funding sources, the Chinese studies (2.1% vs. 34.2%, P < 0.001) and the affiliated institutions of researchers (37.5% vs. 72.2%, P < 0.001) markedly increased in the contemporary years from the past Western studies and non- profit organization, respectively. The robust radiation techniques were more usual in the contemporary years (11.5% vs. 44.9%, P < 0.001). The fractionation schedule and delivery technique were the common issues in both past and contemporary years of Category A. In Category B, the indications of stereotactic radiotherapy was the rising concern, with eight ongoing studies. Except for the studies of palliative or prophylactic goals and stereotactic radiotherapy, the escape from conventional fraction size was 37.9% (36/95) in the contemporary years with the median fraction size of 2.5 Gy (range 2.05–6.6 Gy) in the comparison with 19.0% (15/79) in the past years (P = 0.006). Conclusions: To activate the clinical trials for radiotherapy, the funding sources would be diversified, including industrial support. Hypofractionated schedules using robust techniques could be preemptively considered in actual clinical practice. Keywords: Radiotherapy, Clinical trials, Hypofraction, Stereotactic radiotherapy Introduction accelerators [1]. Currently, the radiotherapy usage rates Radiotherapy has had a long-term history of over a hun- as the first course of treatment reached about 31% in US dred years of treating malignant cancer after X-rays and 2014 statistics [2]. However, for better clinical outcomes radium were discovered at the end of the nineteenth through qualified radiotherapy, a radiation oncologist century. Initially, radium and low-energy machines were must understand the place of radiotherapy and cooper- used for the easily accessible tumors and radiotherapy ate with the surgical and medical oncologists in this era began to expand the field to all malignant cancers of multidisciplinary approaches. thanks to the generalization of mega-voltage linear Clinical trials systematize the usefulness of individual clinical experience and distinguish the values of specific treatments. The well-designed randomized controlled * Correspondence: irionyws@korea.ac.kr clinical trials can establish the evidence-based medicine Radiation Oncology, Ansan Hospital, Korea University, 123 Jeokgeum-ro, Danwon-gu, Ansan, Gyeonggi-do 15355, Republic of Korea © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Park et al. Radiation Oncology (2020) 15:36 Page 2 of 7 to guide the standard management and to suggest future Category C: The studies to investigate supplementary strategies. Actually, the phase III clinical trials which agents (management) to support the therapeutic were completed before a decade would construct the effectiveness and tolerability of radiotherapy, and present clinical guideline in consideration of the mature Category D: The studies to investigate optimal partners period. In addition, through the overview of the recent of pharmaceutical agents or procedures with clinical trials, the emerging issues could be well identi- radiotherapy. fied. For optimal radiotherapy, there is no better method than to look back at the implemented and implementing The information on protocol number, study status, clinical trials with radiotherapy. disease conditions, radiotherapy aim, the endpoints, Hence, we reviewed the features of phase III clinical sponsor/collaborators, study location, and the details of trials in the past and contemporary radiotherapy. Conse- radiotherapy, surgery, and pharmaceutical agents was quently, the radiation oncologists could figure out the collected from the web page of “ClinicalTrials”. If the de- context of change and existing problems, and get advice tails of treatments for each study were insufficient, the on actual clinical practice and future clinical trials. In open information was collected from the web sites addition, the directions to further activate clinical re- “Pubmed” and “Google” using protocol number and searches could be discussed in radiation oncology. other ID of trials. The main end-points of this study were (1) to measure the volume of clinical trials regarding radiotherapy, (2) Methods to observe the changes of funding sources and study lo- For searching for information on clinical trials, we used cations, (3) to consider the change of radiation schedule the database of ‘ClinicalTrials.gov’ by the U.S. National and fraction size, and (4) to check the application of the Institute of Health. The clinical trials of phase III includ- state-of-the-art techniques. A Chi-square test was con- ing the term “Radiotherapy” were searched for in terms ducted to compare the difference of the past and con- of all study statuses (recruiting/ enrolling by invitation/ temporary years. A two-sided p < 0.05 was considered active, not recruiting/ suspended/ terminated/ com- significant. SPSS 20.0 (IBM SPSS, Inc., Chicago, IL) was pleted/ withdrawn/ unknown status) except for the sta- used for the analysis. tus of “not yet recruiting”. The starting date of the study was limited from Jan 2000 to Dec 2003 and from July Results 2014 to June 2018. The eligible criteria were studies in Of the total of 206 past and 351 contemporary studies, 96 which (1) radiotherapy had an obvious role for the and 158 studies satisfied our eligibility criteria for our therapeutic outcomes, (2) radiotherapy was done for a studies, respectively. (Figure 1) The number of phase III malignant cancer including borderline malignancies, and clinical trials regarding radiotherapy increased by 64.6% in (3) external beam radiotherapy was applied in any arm. the contemporary years. While Category A increased by The exclusion criteria were studies in which (1) the sub- 6.2% in the contemporary years in comparison with the ject was hematologic or lymphatic malignancies or only past years, however, the difference was not remarkable children, (2) the stratification was done after performing (P = 0.309). One and three studies in the past and contem- radiotherapy, (3) the effectiveness of neoadjuvant or con- porary years had to be included in both categories, be- solidative management that did not involve radiotherapy cause they were designed by the 2 X 2 fractions model, was investigated without the change of radiotherapy protocol in all allocated arms, and (4) the details of hor- monal therapy, such as drug combination, duration and timing, were investigated in breast and prostate cancer. First, to know the patterns during each period of 4 years, the past years (Jan 2000 to Dec 2003) and the con- temporary years (July 2014 to June 2018) studies were divided according to the start date of the study. Second, the studies were classified with four categories in terms of the investigating subjects as below. Category A: The studies to compare rival radiotherapy protocols, (e.g. treatment schedule, radiation field, or techniques), Fig. 1 Flow of selection process from all phase III studies with the Category B: The studies to compare the standard keyword “radiotherapy” to eligible studies therapy and new ones in multidisciplinary approaches, Park et al. Radiation Oncology (2020) 15:36 Page 3 of 7 and all four studies were associated with category A. The After excluding the studies with palliative or prophy- primary radiotherapy was intended to cure the actual tu- lactic aims and applying SBRTs, 79 and 95 studies of the mors in 58.3 and 63.9% of the past and contemporary past and contemporary years, respectively, addressed studies, respectively (P = 0.299). The studies administering their fraction schedule of radiotherapy in protocols. The concurrent chemotherapy were used in the past years of escape from conventional daily fraction size of 1.8–2Gy 54.1% and contemporary years of 63.3% (P =0.350). was 19.0% (15/79, 5 hyperfraction regimen) in the past Whereas the past studies was done in Western areas and years and 37.9% (36/95, 1 hyperfraction regimen) in the supported by non-profit organizations, the studies from contemporary years (P = 0.006). In terms of CCRT China and affiliated institutions of the researcher mark- protocol, 14.6% (7/48, 5 hyperfraction regimen) and edly increased in the contemporary years (both P <0.001). 27.3% (21/77, 1 hyperfraction regimen) of studies used a The weak industrial supports were unchanged in the past daily fraction size higher than 2 Gy in the past and con- (7.3%) and contemporary (8.9%) years. For the endpoints, temporary years, respectively (P = 0.098). The median the toxicity was more commonly observed in contempor- fraction size of hypofraction was 2.5 Gy (range 2.05–6.6 ary years (P =0.003) (Table 1). Gy) and 2.3 Gy (range 2.12–5.0 Gy) in whole and CCRT The contemporary studies in Category A were con- studies in the contemporary years, respectively (Fig. 3). cerned with the fractionation schedule in 43.5% (20/46) of cases without the significant change of detailed pat- Discussion terns. (Fig. 2) The applications of hypofraction schedules Although the phase III studies concerning radiotherapy was expanded from rectal and prostate cancers of the were abundantly registered, their increasing rates were not past years to breast, lung, esophagus, and head and neck surprising in comparison with the growth rates of all fields of the contemporary years, and the median fraction size concerning cancer. In the same periods of the past and of the experimental group was 2.66 Gy (range 2.05–5 contemporary years, the registered phase III clinical trials Gy) if one stereotactic body radiotherapy (SBRT) was ex- to be searched for with the keyword of “cancer” doubled, cluded. However, it was not observed to use hyperfrac- from 827 studies to 1674 studies on the database of ‘Clini- tion schedules in the contemporary years. Meanwhile, calTrials.gov’. Of course, that is related to the growing the dose escalation of prostate cancer was investigated market for pharmaceutical agents in malignancy treat- in the past years; the dose de-escalation of human papil- ment, and the industrial sponsors strongly supported ap- lomavirus (HPV) positive head and neck cancer was ex- proximately a third (286/827) of the studies in past years amined in contemporary years. The studies regarding and half of the studies (757/1674) in the contemporary dose prescription advised by positron emission tomog- years. On previous report to analyze oncologic trials re- raphy (PET) were noticeable in lung, head and neck and gardless of the phases of study during recent 10 years, the cervical cancer (Supplementary 1). radiotherapy trials consisted of only 5.3% of whole trials Of the category B, to decide the optimal strategies of and received a week industrial support of 5.8% [3]. multidisciplinary approaches, a few changes were found. How can the studies about radiotherapy be more ac- In the past years, the main concerns were concurrent tively performed? The phase III studies of 2 X 2 frac- chemoradiotherapy (CCRT) vs. radiotherapy or chemo- tional stratification, we guess, could be a good model. therapy alone (13 studies) and additional consolidation For example, RTOG 0617 studies examined total radi- therapy after radiotherapy (7 studies). Currently, the ris- ation dose and usefulness of cetuximab in advanced- ing concerns were additional radiotherapy using SBRT stage lung cancer [4], and four studies in our review, (8 studies) in oligometastases, brain metastases, and he- including NCT00024349 (CRC-BC2001) for bladder can- patocellular carcinoma, and the comparison of adjuvant cer, applied this stratification [5, 6]. Of course, these vs. neoadjuvant therapies (6 studies) in soft tissues, kinds of protocols need more eligible numbers to inhibit stomach, rectal, and penile cancer. the under-power of statistics and thus, they need more For category C, the radio-sensitizers, general tolerability time and cooperation between physicians to publish the or pain and specific toxicity were equally examined in the final outcomes, in addition to the effort to make well- past years. The contemporary concerns were intensified in designed protocols. However, it is more economical to the areas of acute toxicity, such as mucositis, skin reaction reduce the duplicated labors and costs of clinical trials if and urinary symptom. For Category D, new pharmaceut- the eligible condition to investigate is similar. From this ical agents were actively reflected in the contemporary viewpoint, the communication of radiation oncologists years. Whereas most studies were on the traditional and other oncologists could be necessary to clarify the chemo-agents (77.8%, 14/18) in the past years, the studies specific details for radiotherapy and multidisciplinary administering targeted agents, immunotherapy and antivi- management earlier. The industrial funds to plan new rals (41.4%, 12/29) caught up much of the chemo-agents pharmaceutical agents could also be indirectly used for in contemporary years (Table 2). radiotherapy. Park et al. Radiation Oncology (2020) 15:36 Page 4 of 7 Table 1 Studies’ characteristics in the past and contemporary years Past years (Jan 2000 – Dec 2004, N = 96) Contemporary years (July 2014 – June 2018, N = 158) P value Category A 22 (22.9%) 46 (29.1%) 0.309 B 39 (40.6%) 64 (40.5%) 0.807 C 18 (18.8%) 22 (13.9%) 0.306 D 18 (18.8%) 29 (18.4%) 0.937 Aim of radiotherapy Adjuvant 27 43 0.875 Definite 56 82 0.299 Neoadjuvant 11 19 0.892 Palliative 7 21 0.139 Prophylactic 2 4 Any 1 1 Disease status Non-: Metastatic: Any 86: 6: 4 133: 23: 2 0.065** Naïve: Recurrent: Any 88: 1: 7 135: 2: 21 1.000** Sponsors/Collaborators Non-Profitable organization 67 47 < 0.001 Industry 8 14 0.885 Institution of researcher 36 114 < 0.001 Locations < 0.001 Western: China: World-wide: Others 82: 2: 5: 7 76: 54: 10: 18 Participant Institutions 0.770 Single: Multiple 27: 69 41: 117 Concurrent administration of drugs 0.350** Yes: No: Not specified 53: 40: 3 100: 58: 0 Robust delivery technique 11 71 < 0.001 SBRT 3 22 IMRT 8 48 Proton 0 3 Endpoints Survival 76 129 0.627 Tumor response 33 33 0.017 Toxicity 52 114 0.003 Quality of life 40 70 0.681 duplicated with other sub-items **Chi-square tests were conducted excluding “any” or “non-specified” items Category A: to compare rival radiotherapy protocols, B: to compare the strategies in multidisciplinary approaches, C: to investigate supplementary agents for radiotherapy and D: to investigate optimal partners with radiotherapy Western area included USA, Canada, European countries, Australia and New Zealand SBRT Stereotactic body radiotherapy, IMRT Intensity modulated radiotherapy The expansion of clinical trials to non-Western countries National Clinical Trials Network could insure the quality of could be welcome. It can increase the number of studies studies for radiotherapy through the structure name librar- and give more clinical information for the more frequently iesand software toolsand templatesinthe US [7]. developed malignancies in non-Western countries. How- Thanks to intensity modulated radiotherapy (IMRT) tech- ever, to insure the quality of studies, it is necessary to trans- niques and the concept of simultaneous integrated boost to fer the know-how and settle for an efficient system in these intensify the radiation dose on the restricted local area, a emerging locations. It is a typical model that the alliance of hypofractionated schedule would be the inevitable trend for Park et al. Radiation Oncology (2020) 15:36 Page 5 of 7 Fig. 2 The number of studies that compared rival radiotherapy protocols doubled, from 22 in past years to 46 in contemporary years. The two main issues were fraction size and radiation technique in both the past and contemporary years radiotherapy, making it more comfortable for patients by re- favored the SBRT over open surgery in brain metastases ducing the treatment period while showing equivalent clin- and lobectomy in early lung cancer [10, 11]. The clinical ical outcomes. It is notable that the median 2.5 Gy was outcomes were prospective in a phase I/II trial of hepatocel- applied in approximately one third of the contemporary tri- lular carcinoma [12] and an initial trial of oligometastases in als. The SBRT technique broadened its areas from brain prostate cancer [13], and the relevant studies using SBRT metastases to early-stage lung cancer, oligometastases, and could be continued. Additionally, the prescription guidance hepatocellular carcinoma. Through the robust advance of by PET is interesting for achieving a personalized hypofrac- linear accelerators [8], liniac-based stereotactic radiosurgery tion schedule. It was feasible in the initial reports of head rapidly disseminated in brain metastases in the US [9]. and neck cancer, non-small-cell lung cancer, and esophageal There were a few reports about cost effectiveness that cancer [14–17]. Table 2 Investigations’ characteristics in category C and D Past years (Jan 2000 – Dec 2004) Contemporary years (July 2014 – June 2018) P value Category C 0.364 Sensitizer 6 4 General tolerability or Pain 6 6 Specific toxicity 6 12 - Skin reaction - 1 - 4 - Oral mucositis - 3 - 7 - Xerostomia - 2 - 0 - Urinary symptom - 0 - 1 Category D 0.002 Cytotoxic drug 14 17 New drug 2 12 - Targeted agent - 2 - 8 - Immunotherapy - 0 - 3 - Antivirals - 0 - 1 Surgery 2 0 Park et al. Radiation Oncology (2020) 15:36 Page 6 of 7 Fig. 3 Studies using hyper- or hypo-fractional radiotherapy. Hyperfraction schedules for lung, head and neck, and bladder cancer were tried in past years (left panel), but the interests decreased in contemporary year (right panel). Hypofraction schedules were newly tried for breast and hepatobiliary cancer in contemporary years. * The studies applying a hyperfraction schedule were indicated below the line of 2.0 Gy The phase III clinical trials were designed on the basis because of the bulk loading to review all clinical trials of the positive outcomes of early phase studies or credible from 2000 to 2018. Therefore, it would be sufficient to observations. If the progress of experimental investigations see the landscape of clinical trials regarding radiotherapy is active both in quality and in quantity, there would be and prepare for future studies. some portions to preemptively consider those practice case by case. Surely, other experts suggested that the cost- Conclusion effectiveness of new strategy preferentially is assessed [18]. The number of clinical trials consistently increased in We thought that the above mentioned trends of hypofrac- non-Western area, especially. To more activate the clin- tion schedule using IMRT, SBRT and the collaboration ical trials for radiotherapy, it is necessary that the fund- with novel image technologies could be major candidates. ing sources should be diversified, including industrial The therapeutic ratio for late toxicity could be an in- support. Hypofractionated schedules using robust tech- teresting viewpoint in the comparison of the past and niques which were investigated in the contemporary contemporary studies. Meanwhile, the radiation protec- years could be preemptively considered in actual clinical tors of amifostine and supplementary agents of salagen practice for various kinds of cancer. Radiation oncolo- used for reducing late toxicity, such as xerostomia, the gists have to understand the trends of clinical trials for hippocampal-sparing brain radiotherapy using the IMRT radiotherapy and try the next well-designed clinical tri- technique [19], and the dose de-escalation in HPV pa- als. Keeping in mind the place of radiotherapy in multi- tients using biomarkers [20], were actively tried in the disciplinary approaches overall, the cooperation with contemporary years. The supplementary agents focused medical and surgical oncologists would effectively pro- on acute and subacute toxicity of oral mucosa and skin. mote better clinical trials and establish the evidence for One may also wonder whether the synergistic effects of radiotherapy sooner. the combination of radiotherapy and immunotherapy could replace the cytotoxic chemotherapy [21]. Supplementary information There were a few limitations of this review. First, re- Supplementary information accompanies this paper at https://doi.org/10. searchers reported on their studies freely on the plat- 1186/s13014-020-01489-4. form of “ClinicalTrials.gov” and the records were largely Additional file 1: Supplementary 1. The details of investigations in faithful. However, there was some missing information category A (comparison of rival radiotherapy protocols). we wanted to collect, especially in the past years. Sec- ond, there was a possibility that we missed studies, be- Abbreviations cause we used only the platform of “clinical trial,” CCRT: Concurrent Chemoradiotherapy; HPV: Human Papillomavirus; although it is the best known one in the world. Last, we IMRT: Intensity Modulated Radiotherapy; PET: Positron Emission Tomography; observed the studies by the cross-sectional method SBRT: Stereotactic Body Radiotherapy Park et al. Radiation Oncology (2020) 15:36 Page 7 of 7 Acknowledgements 14. 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Radiation Oncology – Springer Journals

Published: Feb 14, 2020

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