Navigating the highlights of phase III trials: a watchful eye on evidence-based radiotherapy

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Navigating the highlights of phase III trials: a watchful eye on evidence-based radiotherapy

Jc Trone, S. Espenel, A. Rehailia-Blanchard, E. Guillaume, N. Vial, C.

Rancoule, C. Rodriguez-Lafrasse, M. Ben Mrad, A. El Meddeb Hamrouni, E.

Ollier, et al.

To cite this version:

Jc Trone, S. Espenel, A. Rehailia-Blanchard, E. Guillaume, N. Vial, et al.. Navigating the highlights

of phase III trials: a watchful eye on evidence-based radiotherapy. Annals of Oncology, Elsevier, 2017,

28 (11), pp.2691 - 2697. �10.1093/annonc/mdx347�. �hal-01690827�

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REVIEW

Navigating the highlights of phase III trials: a watchful eye on evidence-based radiotherapy

J. C. Trone

¹

, S. Espenel

^1,2

, A. Rehailia-Blanchard

¹

, E. Guillaume

¹

, N. Vial

¹

, C. Rancoule

^1,2

,

C. Rodriguez-Lafrasse

²

, M. Ben Mrad

¹

, A. El Meddeb Hamrouni

¹

, E. Ollier

³

, C. Chargari

⁴

, E. Deutsch

⁴

, A. Vallard

^1,2

* & N. Magne´

^1,2

1Department of Radiation Oncology, Lucien Neuwirth Cancer Institute, Saint-Priest-en-Jarez;²Laboratory of Cellular and Molecular Radiobiology, Institut de Physique Nucle´aire de Lyon, IPNL, Villeurbanne;³SAINBIOSE U1059, Jean Monnet University, Saint-Etienne;⁴Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France

*Correspondence to: Dr Alexis Vallard, Department of Radiotherapy, Lucien Neuwirth Cancer Institute, 108 Bis, Avenue Albert-Raimond, BP 60008, 42271 Saint-Priest en Jarez, France. Tel:þ33-4-77-91-74-34; Fax:þ33-4-77-91-71-97; E-mail: alexis.vallard@icloire.fr

Background: Phase III randomized controlled trials (RCTs) are the cornerstone of evidence-based oncology. However, there is no exhaustive review describing the radiotherapy RTCs characteristics. The objective of the present study was to describe features of all phase III RCTs including at least a radiation therapy.

Methods and materials: Requests were performed in the Medline database (via PubMed). The latest update was performed in April 2016, using the following MESH terms: ‘clinical trials: phase III as topic’, ‘radiotherapy’, ‘brachytherapy’, as keywords.

Results: A total of 454 phase III RCTs were identified. Studies were mainly based on open (92.1%) multicenter (77.5%) designs, analyzed in intend to treat (67.6%), aiming at proving superiority (91.6%) through overall survival assessment (46.5%). Most frequently studied malignancies were head and neck (21.8%), lung (14.3%) and prostate cancers (9.9%). Patients were mainly recruited with a locally advanced disease (73.7%). Median age was 59 years old. Out of 977 treatment arms, 889 arms experienced radiotherapy, mainly using 3D-conformal radiotherapy (288 arms, 32.4%). Intensity-modulated techniques were tested in 12 arms (1.3%). The intervention was a non-cytotoxic agent addition in 89 studies (19.6%), a radiation dose/

fractionation modification in 74 studies (16.3%), a modification of chemotherapy regimen in 63 studies (13.9%), a chemotherapy addition in 63 studies (13.9%) and a radiotherapy addition in 53 trials (11.7%). With a median follow-up of 50 months, acute all- grade and grade 3–5 toxicities were reported in 49.6% and 69.4% of studies, respectively. Radiotherapy technique, follow-up and late toxicities were reported in 60.1%, 74%, and 31.1% of studies, respectively.

Conclusion: Phase III randomized controlled trials featured severe limitations, since a third did not report radiotherapy technique, follow-up or late toxicities. The fast-paced technological evolution creates a discrepancy between literature and radiotherapy techniques performed in daily-routine, suggesting that phase III methodology needs to be reinvented.

Key words: radiotherapy, brachytherapy, clinical trials: phase III, review

Introduction

Evidence-based oncology is founded on information provided by clinical trials. Randomized clinical trials (RCTs) procure the highest level of evidence and lead the way to new anticancer treat- ments [1]. Phase I clinical studies are designed to assess the safety profile of therapies. Phase II trials evaluate the therapeutic index (efficacy/toxicity ratio), allowing therapies to be further investi- gated or not. Phase III studies are designed to compare experi- mental treatments versus gold standards, either to prove

equivalence or superiority. Toxicity reporting through standar- dized scales is also a major end point, highlighting acute and late toxicities of experimental therapeutic programs [2].

The benefit of innovative radiotherapy (RT) techniques should theoretically be proven in phase III randomized studies.

However, since radiotherapy does not meet the same prescription

rules as oncologic drugs, modern techniques [intensity modu-

lated radiotherapy (IMRT), volumetric modulated arc-therapy

(VMAT), stereotactic body radiotherapy (SBRT), etc.] were im-

plemented without a clear knowledge of their therapeutic index

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[3]. To our best knowledge, an exhaustive literature review describing the essential characteristics of radiotherapy phase III trials has never been carried out. Yet, this is the only way to know what radiation practices were validated in randomized phase III studies. Furthermore, the identification of patient characteristics and of main trials’ biases are necessary conditions to be able to criticize their methodology and respect their limits [4, 5]. Finally, an update on what has been accomplished in phase III radiother- apy trials would help to identify the future challenges of radiation oncology research.

The aim of the present study was to describe and analyze all randomized phase III clinical trials including at least a radiation therapy.

Methods and materials

Requests were performed in the Medline database (via PubMed) to identify all publications of phase III RCTs analyzing radiation therapy between 1993 (first RCT) and 2016. The latest update was performed in April 2016, using the following MESH terms:

‘clinical trials: phase III as topic’, ‘radiotherapy’, ‘brachytherapy’, as keywords and ‘English’ as limit. Reviewing lists of reported RCT from large cooperative groups such as EOTRC, NSABP, RTOG, SWOG, NCIC, TROG and GORTEC were analyzed to en- sure major studies have not been omitted. References were crossed with clinicaltrials.gov to identify RCT noting some older trials that could have not been included in such registries.

Study selection

Phase III trials were eligible for inclusion if cancer patients (includ- ing malignant blood diseases) were prospectively recruited and if at least one of the randomly assigned treatment included radio- therapy and/or brachytherapy. Exclusion criteria were: radiophar- maceutical trials, non-randomized design, absence of available full text, and sole abstracts. In case of several publications for the same trial, only most recent data were considered. A first selection was conducted based on title and abstract. Then eligible articles were selected on full text and reviewed. Selections were carried out inde- pendently by two reviewers. Concordant articles were included in analysis by the first reviewer and disagreements between the two selections were resolved by a third reviewer.

Data collection

For each selected trial, two different reviewers collected the follow- ing data: journal’s name, year of publication, number of participat- ing centers (mono/multicenter study), design of the study (open versus double-blind; superiority versus non-inferiority), intention to treat analysis (ITT) (yes/no), median follow up, primary end point (overall survival, progression-free survival, disease-free sur- vival, distant progression, local control, biochemical failure, tox- icity, quality of life, pain palliation), experimental hypothesis, number of included patients, cancer(s) type, stage (early disease, locally advanced, metastasis), median age, radiotherapy fraction- ation (standard fractionation: 1.8–2.2 Gy), radiotherapy tech- nique, radiotherapy dose escalation (yes/no), concurrent chemotherapy (CT) administration (yes/no), cytotoxic agents’

name, concurrent non-cytotoxic agent (NCA: including targeted

therapies, immunotherapies, hormonotherapies and other agents such as radiosensitizing or radioprotective agents) administration (yes/no), NCA name, acute all grades and acute grade 3–5 toxic- ities [yes/no, evaluated by the National Cancer Institute Common Toxicity Criteria (CTCAE v3.0)], late (>3 months) toxicities (yes/

no), quality of life (yes/no) and industrial sponsorship.

Statistical analysis

A descriptive analysis of the results was realized. Median values were given with their interquartile ranges and their minimum and maximum values.

Results

Literature selection

Initial research resulted in 1254 hits. After a first selection on title and abstract, 707 full-text reports were assessed for eligibility.

After duplicates suppression, 454 studies met inclusion and ex- clusion criteria and were analyzed (Figure 1).

Studies characteristics

Data of 454 RCTs were collected, with 39.9% of recent (2011–

2016) publications. Most of studies were published in five jour- nals: Journal of Clinical Oncology (22.2%), International Journal of Radiation Oncology-Biology-Physics (18.1%), Radiotherapy and Oncology (12.1%), Lancet Oncology (9.9%) and Annals of Oncology (4.6%).

Studies were mainly based on open (92.1%) multicenter (77.5%) designs. Most of trials were conducted in ITT (67.6%).

The intervention was an NCA addition in 89 studies (19.6%), a modification of radiation dose/fractionation in 74 studies (16.3%), a modification of cytotoxic regimens in 63 studies (13.9%), a chemotherapy addition in 63 studies (13.9%) and a radiotherapy addition in 48 trials (11.2%). The goal of studies was to prove superiority in 91.6% of trials. Main primary end points were overall survival (46.5%), progression-free survival (20.5%), toxicity (13.9%), local control (10.1%) and disease-free survival (8.4%). Funding sources were not available in 13.2% of publications. Studies characteristics are reported in Table 1.

Patient characteristics

The median number of patients included per study was 256 (Q1–

Q3: 130–446; min–max: 19–5318), with a median age of 59 years (Q1–Q3: 55–63; min–max: 7.9–86.3). Median age was not re- ported in 85 trials (18.7%). Patients were randomized with a lo- cally advanced disease (73.7%), an early stage disease (39.6%), or at a metastatic setting (9.0%). The most analyzed primary loca- tions were head and neck (21.8%), lung (14.3%), breast (10.1%), prostate (9.9%), colorectal cancer (7.5%), brain (7.3%) and cer- vix (7.0%). Patient characteristics are reported location by loca- tion in Table 2.

Data on treatment

The 454 studies included 977 treatment arms, with 889 arms experiencing radiotherapy. A total of 324 trials (71.4%) studied

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the association of radiation with other treatments and 130 trials (28.6%) investigated exclusive radiotherapy. A radiation dose- escalation was performed in 36 studies (7.9%). Radiation tech- nique was exclusively 3D-conformal radiotherapy in 288 arms (32.4%), a radiation technique association (brachytherapy asso- ciated with external beam radiotherapy or 3D conformational radiotherapy associated with SBRT) in 73 arms (8.2%), and ex- clusively intensity-modulated radiotherapy in 12 arms (1.4%).

Different radiation techniques were accepted in 70 arms (7.8%).

Radiotherapy technique was not described in 355 arms (39.9%).

Normo-fractionation (1.8–2.2 Gy/fraction) was performed in 648 arms (72.9%), hypofractionation in 107 arms (12.0%) and hyperfractionation in 71 arms (8.0%). Normofractionated versus hypo/hyperfractionated programs were compared in 63 studies (13.9%). Radiotherapy characteristics are reported in Table 3.

Chemotherapy was performed in 257 studies (56.6%), result- ing in 444 arms. Chemotherapy was delivered with concurrent radiotherapy in 303 arms (68.2%). Cisplatin (219 arms, 49.3%), 5-fluorouracil (128 arms, 28.8%), carboplatin (49 arms, 11.0%), and etoposide (47 arms, 10.6%) were mainly prescribed.

Chemotherapy characteristics are summarized in Table 4.

An NCA was prescribed in 113 studies (24.9%), resulting in 147 treatment arms. Main NCAs were hormonal interventions (20 arms, 13.6%), targeted therapies (18 arms, 12.2%), and immunotherapies (9 arms, 6.1%). NCA were most of the time concomitantly associated with radiotherapy (124 arms, 84.3%).

NCA characteristics are detailed in Table 5.

Follow-up, toxicities and quality of life

Median follow-up was 50 months (Q1–Q3: 29–73; min–max:

1–127), with 118 studies (26%) not reporting it. Quality of life was evaluated in 118 studies (26.0%). Acute all-grade and acute grade 3–5 toxicities were reported in 225 studies (49.6%) and in 315 studies (69.4%), respectively. Data on late toxicities were re- ported in 141 studies (31.1%). Data on toxicities are reported in Table 6.

Discussion

Although analyses of phase I and II radiotherapy trials were previ- ously conducted [6, 7], the present manuscript is the first analysis of phase III randomized radiotherapy studies. Justifications and limitations of real-world practices in radiation oncology are highlighted.

Radiotherapy RCTs should be considered as recent develop- ments, since the two-thirds were published in the last decade and only 14.3% before 2000. Most of analyzed trials were exclusively based on 3D conformational radiotherapy. Comparison of in- novative techniques (IMRT, VMAT, SBRT) versus 3D conform- ational radiotherapy was rarely performed (<2%). Therefore, efficacy and toxicity results obtained with 3D conformational radiotherapy should be cautiously extrapolated to other tech- niques in the absence of RCT. For instance, the bath-dose phe- nomenon (large healthy tissue volume receiving low radiation Records identified based on

keywords (N=1254)

217 excluded :

• Active trials

• Trial already published

• Observational studies

• Phase II

547 trials excluded :

Identification and screeningEligibilityIncluded

• Phase I/II studies

• Observational/non randomized studies

• Sub group from another study Records screened

(N=1254)

Randomized controlled studies eligible

(N=490)

Full text articles assessed for eligibility

(N=707)

Randomized controlled studies included

(N=454)

36 excluded :

• Full text article not available

Figure 1. CONSORT ﬂow diagram.

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Table 1. Characteristics of included studies (n 5 454 studies)

Trials characteristics Number of studies (%) Journal

Journal of Clinical Oncology 101 (22.2) International Journal of Radiation

Oncology-Biology-Physics

82 (18.1)

Radiotherapy and Oncology 55 (12.1)

Lancet Oncology 45 (9.9)

Annals of Oncology 21 (4.6)

NEJM 20 (4.4)

Lancet 14 (3.1)

Gynecologic oncology 12 (2.6)

Cancer 10 (2.2)

Other 94 (20.8)

Year of publication

2011–2016 181 (39.9)

2006–2010 126 (27.7)

2001–2005 82 (18.1)

2000 65 (14.3)

Number of participating centers

Multicenter 352 (77.5)

Single center 78 (17.2)

Unknown 24 (5.3)

Number of patients per trial, median (Q1–Q3, min–max)

256 (130–446, 19–5318) Sources of trial funding

No industry funding 311 (68.5)

Industrial sponsorship 83 (18.3)

Unknown 60 (13.2)

Blinding

Open 418 (92.1)

Double-blind 36 (7.9)

Subject studied

Non-cytotoxic treatment addition 89 (19.6) Radiation dose/fractionation modiﬁcation 74 (16.3) Chemotherapy regimen modiﬁcation 63 (13.9)

Chemotherapy addition 63 (13.9)

Radiotherapy addition 53 (11.7)

Radiotherapy technique modiﬁcation 22 (4.8) Chemoradiotherapy addition 11 (2.4)

Other 79 (17.4)

Primary end points^a

Overall survival 211 (46.5)

Progression-free survival 93 (20.5)

Toxicity 63 (13.9)

Local control 46 (10.1)

Disease-free survival 38 (8.4)

Quality of life 19 (4.2)

Pain 8 (1.8)

Distant progression 8 (1.8)

Biochemical failure 5 (1.1)

aThe sum of primary end points exceeds 100% since several studies had multiple primary end points.

Q1–Q3, interquartile ranges.

Table 2. Patient characteristics (n 5 454 studies. Median age was not reported in 85 studies)

Patient characteristics

Median age of patients, years (Q1–Q3; min–max) 59 (55–63; 7.9–86.3) Age distribution, number of studies (%)

>70 years 16 (3.5)

61–70 years 139 (30.6)

51–60 years 160 (35.2)

50 years 54 (11.9)

Unknown 85 (18.7)

Primary tumor location, number of studies (%)

Head and Neck 99 (21.8)

Tumor staging, number of studies (%)

Early disease 4 (0.9)

Locally advanced disease 65 (14.3)

Metastatic disease 0

Mixed disease status^a 30 (6.6)

Median age, years (Q1–Q3; min–max) 55.5 (53.5–57.5; 42–62)

Lung 65 (14.3)

Metastatic disease 3 (0.7)

Median age, years (Q1–Q3; min–max) 63 (60–64; 56.5–77)

Breast 46 (10.1)

Mixed disease status^a 0

Median age, years (Q1–Q3; min–max) 56 (53.5–58.5; 47–69.5)

Prostate 45 (9.9)

Median age, years (Q1–Q3; min–max) 69 (66.5–70; 61–75)

Colorectal 34 (7.5)

Early disease 0

Median age, years (Q1–Q3; min–max) 62 (60.5–63; 55–66)

Brain 33 (7.3)

Early disease 0

Locally advanced disease 0

Median age, years (Q1–Q3; min–max) 55 (42–56.5; 7.9–76)

Cervix 32 (7.0)

Continued

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doses) induced by intensity modulated techniques might be re- sponsible for late toxicities (fibrosis, radio-induced cancers) that will hardly be proven without RCT. Surprisingly, dose or frac- tionation modifications only accounted for 16.3% of analyzed trials. This result is corroborated by the fact that programs that Table 2.

Continued

Patient characteristics

Mixed disease status^a 0

Median age, years (Q1–Q3; min–max) 48 (45–52; 41–64.3) Patients with metastases, regardless of

the primary tumor site

26 (5.7) Median age, years (Q1–Q3; min–max) 60 (58–67; 52–69)

Esophagus/stomach 20 (4.4)

Median age, years (Q1–Q3; min–max) 60.5 (58–62; 56–86.3)

Others 54 (12)

Median age, years (Q1–Q3; min–max) 60 (55–64; 15–74)

aMixed disease status included early disease and/or locally advanced disease and/or metastatic disease.

Q1–Q3, interquartile range.

Table 3. Radiotherapy characteristics (n 5 889 arms of treatment)

Characteristics Number of arms (%)

Radiotherapy technique (in the 889 arm of treatment including a radiotherapy)

3D conformational radiotherapy 288 (32.4)

2D radiotherapy 62 (7.0)

3Brachytherapy 15 (1.7)

IMRT 12 (1.4)

SBRT 4 (0.4)

Other 10 (1.1)

Unknown 355 (39.9)

Technique association

Brachytherapyþexternal beam radiotherapy 64 (7.2) 3D conformational radiotherapyþSBRT 9 (1.0) Multiple techniques allowed

3D/IMRT 33 (3.7)

2D/3D 25 (2.8)

Other 12 (1.4)

Fractionation (in the 889 arm including a radiotherapy)

Normo-fractionation 648 (72.9)

Hypo-fractionation 107 (12.0)

Hyper-fractionation 71 (8.0)

Multiple fractionation programs allowed 32 (3.6)

Unknown 31 (3.5)

Except for brachytherapy, all other techniques were based on external beam radiotherapy.

IMRT, intensity-modulated radiotherapy; SBRT, stereotactic body radiotherapy.

Table 4. Cytotoxic agents characteristics (n 5 444 arms of treatment)

Characteristics Number (%)

Chemotherapy administration in RCTs

Yes 257 (56.6)

No 197 (43.4)

Chemotherapy administration characteristics (in the 444 arms including a chemotherapy)

Concurrent association with radiotherapy 222 (50.0) Sequential association with radiotherapy 96 (21.6)

Before radiotherapy 72 (16.2)

After radiotherapy 24 (5.4)

Combination of sequential and/or concurrent administration

Concurrent association AND sequential association 81 (18.2)

Other 8 (1.8)

Not associated with radiotherapy 33 (7.4)

Unknown 4 (1.0)

Cytotoxic agents used (in the 444 arms including a chemotherapy)

Cisplatin 219 (49.3)

5-Fluorouracil 128 (28.8)

Carboplatin 49 (11.0)

Etoposide 47 (10.6)

Paclitaxel 29 (6.5)

Vincristine 28 (6.3)

Doxorubicin 27 (6.1)

Mitomycin C 22 (4.9)

RCT, randomized controlled trial.

Table 5. Characteristics of non-cytotoxic agents (NCA) (n5 147 arms of treatment)

Characteristic Number of arms (%)

Non-cytotoxic agents association with radiotherapy (in the 147 arms including an NCA)

Concurrent association with radiotherapy 103 (70.0)

After radiotherapy 11 (7.5)

Before radiotherapy 6 (4.1)

Combination

Concurrent PLUS before/after radiotherapy 21 (14.3)

Other 1 (0.7)

Not associated with radiotherapy 5 (3.4) Non-cytotoxic agents used (in the 147 arms including an NCA)

Hormone manipulations 20 (13.6)

Targeted therapy 18 (12.2)

Immunotherapy 9 (6.1)

Other (radiosensitizing agents and radioprotective agents)

100 (68.1)

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are widely used in daily routine have been only been very recently [8] validated with RCTs, or will soon be [9]. Radiation technique comparison was rare (4.8%), most of trial rather testing different global managements of care. Rightly or wrongly, the radiation technique is not expected to produce major variation regarding primary end points, but this assertion is still to be demonstrated.

The population included in trials was younger than daily rou- tine patients undergoing radiotherapy [10], with only 16 RCTs reporting a median age >70 years. Major differences were re- ported in lung cancer patients (RCTs median age ¼ 63 versus 70 in real-life patients) and in head and neck cancer patients (RTCs median age ¼ 55.5 versus 62 in real-world patients).

Extrapolation of studies results in the real-world population might therefore sometimes be questionable [11]. Furthermore, the literature sorely lacks trials studying adapted-to-elderly radio- therapy programs since oncogeriatric scales use does not define new target volumes, new radiation doses/fractionations, or per- sonalized concurrent chemotherapy protocols. Head and neck carcinoma was the most analyzed primary location (21.8%) even though it is only the sixth most common cancer worldwide [12].

The leading place in literature is probably explained by the fact that head and neck is one of the only cancers in which benefits of IMRT [13], and of concurrent targeted therapy were proven [14].

However, although IMRT proved its superiority over 3D-con- formational radiotherapy, most of patients are now treated using VMAT, whose real therapeutic index was recently questioned [15, 16]. This situation highlights the fact that technological pro- gress always remains one step ahead clinical results. This situation is a major problem in good prognoses (breast, prostate, etc.) or rare (cervix, sarcomas, etc.) cancers, since the radiation technique is often considered outdated when definitive results are pub- lished. However, without certainty on long-term efficacy and tox- icity, innovative radiotherapy techniques must be performed (whenever possible) within the framework of clinical trials.

Overall survival was often selected as the primary end point (46.5%). Although it is the gold standard, survival assessment re- quires a large number of patients, a long follow-up and increases the cost of randomized clinical trials [17]. The identification of rele- vant surrogate markers is probably a major challenge of modern on- cology, since future personalized treatment lines will probably differently impact patient overall survival, depending of their gen- etic alterations [18]. Although the goal of most RCTs was to study

the effect of a combination NCA/radiation, more needs to be done, especially regarding the interactions between targeted therapies and radiotherapy. While targeted therapies have been studied in many clinical trials, there is still paucity of data regarding their association with radiotherapy (12.2% of NCA). Numerous trials (>90 in lung cancer) are currently recruiting but an extreme caution is advised while awaiting results [19]. One of the most important challenges of these RCTs is the high-quality reporting of acute and late toxicities.

In our analysis, all-grade and grade 3–5 adverse events were only re- ported in 49.6% and 69.4% of trials, respectively. Worse, late toxic- ities were reported in 31.1% of RCTs, suggesting that the reporting of adverse events remains highly variable and that standards for re- porting need to be improved [20, 21]. To this end, Consolidated Standards of Reporting Trials (CONSORT) statement was de- veloped [22]. Although the quality of reporting in radiation RCTs is poorly described, it is a crucial element to ensure reproducible re- sults [23–25]. The present analysis revealed that 39.9% of radiother- apy programs were not described and that median follow-up was not reported in 26% of publications. These results were corrobo- rated by other authors, suggesting that that numerous CONSORT items were most of the time not reported in radiation oncology tri- als [26, 27]. This lack of reporting of radiation details widely ham- pers the appreciation of the quality of radiation. This point raises serious concern on outcome interpretation since it was demon- strated that deviations from radiation standards on multicenter phase III clinical trials was associated with decreased survival [28, 29]. Therefore, a better reporting of radiation detail is of paramount importance in order to accurately appreciate the quality of radi- ation, and to be able to critically assess reported trials.

RCTs will (and should) remain a key tool in clinical research.

Through a simple portrait of phase III RCTs, the present review suggests that radiotherapy trials must be carefully interpreted since patient population and radiotherapy techniques might differ from daily routine practice, and since reporting quality was often lim- ited. Furthermore, the years to come will probably give birth to a vast possibility of treatment and doses combinations, with differ- ent anticancer agents, immune and targeted therapies and radio- therapy techniques [6]. This will probably reduce the possibility to recruit a large number of patients in randomized two-armed trials.

In this evolving environment, newer trial designs have already been developed, such as those focused on efficiently assessing tar- geted interventions for specific pathway or genomic signatures.

Regarding radiotherapy, integration of mathematic modelling and radiomics data could be probably integrated in the design of future phase III RCTs in order to increase the statistical power. Adapted and well suited methods should probably be now collectively de- signed by investigators, physicians, statisticians and methodolo- gists. Let’s be up for the challenge of reinventing radiotherapy trials, let’s build the future of radiation trials on past evidences.

Funding

None declared.

Disclosure

The authors have declared no conflicts of interest.

Table 6. Data on adverse event reporting (n ¼ 454 studies)

Characteristics Number of studies (%)

Data on follow-up available

Yes 336 (74.0)

No 118 (26.0)

Median follow-up, months (Q1–Q3; min–max) 50 (29–73; 1–127)

Quality of life assessment 118 (26.0)

Description of radio induced events

All grades toxicities 225 (49.6)

Grade 3–5 toxicities 315 (69.4)

Late toxicities 141 (31.1)

Q1–Q3, interquartile ranges.

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