Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Faivre-Finn, 2017

Type of study: CONVERT-trial: open-label, phase 3, randomised, superiority trial

Setting: Between April 7, 2008, and Nov 29, 2013, patients were enrolled from 73 centres in eight countries and randomly assigned to receive twice-daily concurrent chemoradiotherapy or once-daily concurrent chemoradiotherapy.

Country: UK

Source of funding: Cancer Research UK reviewed and approved the study design. None of the funders had a role in data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Inclusion criteria: aged 18 years or older; histologically or cytologically confirmed small-cell lung cancer with limited disease, had an Eastern Cooperative Oncology Group performance status of 0–117 or performance status of 2 due to disease-related symptoms and not co- morbidities had no malignant pleural or peri- cardial effusions; and had acceptable radiotherapy target volume, a maximum of one adverse biochemical factor concentrations of serum alkaline phosphatase >1·5-times the upper limit of normal, serum sodium <lower limit of normal, and serum lactate dehydrogenase >the upper limit of normal), forced expiratory volume in 1 s greater than 1 L or 40% predicted value, and transfer factor for carbon monoxide greater than 40% predicted value.

Exclusion criteria: Patients with a previous history of malignancy in the past 5 years (except for non-melanomatous skin or in- situ cervix carcinoma) and those with previous or concomitant illness or treatment that, in the opinion of the investigator, would interfere with the trial treatments or comparisons were excluded.

N total at baseline: 547

Intervention: 274

Control: 273

Important prognostic factors²:

Age (years):

I: 62 (29-84)

C: 63 (34-81)

Sex:

I: 54% M (n=147)

C: 55% M (N=150)

Eastern Cooperative Oncology Group Perfomrance Status:

0

I: 125 (46%)
C: 123 (45%)

1

I: 137 (50%)
C: 142 (52%)

2

I: 9 (3%)
C: 8 (3%)

Not known:

I: 3 (1%)

C: 0 (0%)

Groups comparable at baseline? Yes

66 Gy radiotherapy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin–etoposide chemotherapy (given as four to six cycles every 3 weeks)

45 Gy radiotherapy in 30 twice-daily fractions of 1.5 Gy over 19 days, starting on day 22 after commencing cisplatin–etoposide chemotherapy (given as four to six cycles every 3 weeks)

Length of follow-up: On completion of study treatment, patients were followed up weekly until the resolution of acute side- effects, then every 3 months until 1 year, and every 6 months for 5 years.

Loss-to-follow-up:

Intervention: N=25

Control: N=33

Reasons: progressive disease or death, too large tumour volume, randomisation error, patient withdrawal/lost to follow-up, chemotherapy toxicity, oncologist decision.

Incomplete outcome data:

Intervention: N=1

Patient did not return case report form.

Control: N=3

Patients did not return case report forms.

Overall survival (time from randomisation until death from any cause, analysed by modified intention-to-treat):

At a median follow-up of 45 months (IQR 35–58), median overall survival was 30 months (95% CI 24–34) in the twice-daily group versus 25 months (21–31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95–1·45]; p=0·14).

2-year overall survival was 56% (95% CI 50–62) in the twice-daily group and 51% (45–57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI –3·2% to 13·7%]).

5-year overall survival was 34% (95% CI 27–41) in the twice-daily group and 31% (25–37) in the once-daily group (absolute difference 2·8% [95% CI –6·4% to 12·0%]).

Acute toxicity (toxicity occuring between the start of tratment and up to 3 months after completion of treatment assessed according to CTCAE):

The most common grade 3–4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3–4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3–4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group).

Local and metastatic PFS: Median progression-free survival was 15.4 months (95% CI 13.7–19.8) in the twice-daily group and 14.3 months (12.0–17.0) in the once-daily group (hazard ratio 1.12 [95% CI 0.92–1.38]; p=0.26). Median local progression-free survival was 20.7 months (95% CI 16.1–27.9) in the twice-daily group versus 17.9 months (15.3–21.7) in the once daily group and median metastatic progression-free survival was 20.2 months (95% CI 15.9–25.3) versus 16.6 months (13.7–21.8). The difference between groups for local progression-free survival (p=0.20) and metastatic progression-free survival (p=0.24) was not significant. There was no notable difference between groups in treatment received at the time of progression.

The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status.

Survival outcomes did not dier between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting.

Response rate was another secondary outcome but it was not analysed because interpretation of CT imaging would have been too complex after concurrent chemoradiotherapy.

Study reference

(first author, publication year)

Describe method of randomisation

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?

(unlikely/likely/unclear)

Bias due to loss to follow-up?

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?

(unlikely/likely/unclear)

Faivre-Finn, 2017

Randomly assignment (1:1) to one of the two treatment groups.

Likely, allocation to treatment group was done by phone call or fax from the recruiting centre.

The factors controlled for in the allocation were institution, planned number of chemotherapy cycles (four vs six), and performance status (0–1 vs 2).

Likely, no blinding

Likely, no blinding

Unclear

Unlikely, but response rate was another secondary outcome but it was not analysed because interpretation of CT imaging would have been too complex after concurrent chemoradiotherapy.

Unlikely

Unlikely

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

De Ruysscher, 2016

SR and meta-analysis of randomized trials

Literature search from 1969 up to end of 2006

A: Perry, 1998

B: Murray, 1993

C: Gregor, 1997

D: Takada, 2002

E: Spiro, 2006

F: Skarlos, 2001

G: Blackstock, 2005

H: Lebeau, 1999

I: Turrisi, 1999

Study design: SR and meta-analysis of RCTs

Setting and Country:

The Netherlands

Source of funding:

The meta-analysis was funded by the French National Cancer Institute (Programme Hospitalier de Recherche Clinique), the Ligue Nationale Contre le Cancer and partly by Sanofi-Aventis (unrestricted grants). The investigators meeting was also funded by Gustave Roussy, Lilly and Astra-Zeneca (unrestricted grants). No grant number is applicable.

Inclusion criteria SR: Trials had to compare two timing schedules of curative thoracic radio-therapy, i.e. earlier versus later within an indi- vidual trial in patients with limited-stage SCLC treated with chemo-radio-therapy. Radiotherapy should have been initiated before 9 weeks after randomization and before the third cycle of CT. Trials comparing two radiotherapy durations, i.e. a shorter versus a longer course within an individual trial with at least a two-week treatment difference observed between the two arms, were also eligible. Trials had to start after 1969 and to end before 2006 and be properly randomized. The planned CT schedule (drugs, doses, number of cycles) had to be the same in both arms, but radiotherapy modal- ities could be different. The total dose of radiotherapy had to be at least 30 Gy.

Exclusion criteria SR: Orthovoltage radiotherapy

12 studies included, 9 in meta-analysis

Important patient characteristics at baseline:

2305, mean age

A: 292;

B: 332

C: 349

D: 231

E: 325

F: 81

G: 114

H: 164

I: 417

Sex (M): I / C:

775 (67%) / 745 (65%)

Age (yrs): I / C:

<60: 474 (41%) / 474 (41%)

60-64: 256 (22%) / 294 (26%)

>65: 419 (36%) / 381 (33%)

Unknown: 4 (0%) / 3 (0%)

Disease extend: I / C:

Limited: 762 (66%) / 796 (69%)

Extensive: 17 (2%) / 4 (0%)

Unknown: 374 (32%) / 352 (31%)

Performance Status (WHO/ECOG): I / C:

0: 449 (39%) / 417 (36%)

1: 602 (52%) / 622 (54%)

2/3: 91 (7%) / 104 (9%)

Unknown: 11 (1%) / 9 (1%)

Groups comparable at baseline? Yes

Earlier or shorter RT

A: 50 Gy/24 fr/5 week, start day 1;

B: 40 Gy/15 fr/3 weeks, start day 22;

C: 12.5 Gy/5 fr/1 week, start day 43;

D: 45 Gy/30 fr/3 weeks bid, start day 2;

E: 40 Gy/15 fr/3 weeks, start day 22;

F: 45 Gy/30 fr/3 weeks bid, start day 1

G: 50 Gy/25 fr/5 weeks

H: 50 Gy/20 fr/5 weeks

I: 5 Gy/30 fr/3 weeks bid

Later or longer RT

A: 50 Gy/24 fr/5 weeks, start day 64

B: 40 Gy/15 fr/3 weeks, start day 106

C: 50 Gy/20 fr/4 weeks, start day 99

D: 45 Gy/30 fr/3 weeks bid, start day 85

E: 40 Gy/15 fr/3 weeks, start day 106

F: 45 Gy/30 fr/3 weeks bid, start day 57

G: 20 Gy/8 fr/2 weeks

H: 20 Gy/8 fr/2 weeks

I: 45 Gy/25 fr/5 weeks

Median follow-up (years):

A: 17.2

B: 11.2

C: 7.2

D: 6.8

E: 5.3

F: 11.8

G: 17.3

H: 6.5

I: 13.0

For how many participants were no complete outcome data available?: NR

Total heterogeneity is the sum of between-subset and residual (within-subset) heterogeneity and is equal to 21.6 (analysis based on nine trials) except for CT compliance 21.4 (eight trials). The test associated with between-subset heterogeneity corresponds to the interaction test. The lower the residual heterogeneity, the greater was the overall heterogeneity of the treatment effect between trials explained by the trial characteristic.

Overall survival defined as the time from randomization until death from any cause or the last follow-up for surviving patients:

HR (95%CI) of death following earlier/shorter versus later/longer RT:

CT compliance between arms:

Similar: 0.79 [0.69–0.91];

Different: 1.19 [1.05–1.34]

-RT dose per fraction:

< 1.8 Gy: 0.82 [0.71–0.96];

1.8-2.4 Gy: 1.11 [0.90–1.35]; >2.4 Gy: 1.06 [0.94–1.20]

-Type of RT:

Hyperfractionated: 0.82 [0.71–0.96];

Standard: 1.07 [0.96–1.19]

-RT overall treatment time:

<30 days in both arms: 0.89 [0.78–1.02];

One arm <30 days, one >30 days: 0.99 [0.85–1.15];

>30 days in both arms: 1.16 [0.98–1.38]

-Platin-based CT in both arms:

Yes: 0.89 [0.79–1.01];

No: 1.09 [0.97–1.24]

-Concurrent CT in both arms:

Yes: 0.95 [0.85–1.06];

No: 1.06 [0.92–1.22]

-Same RT in two arms:

Yes: 0.96 [0.85–1.08];

No: 1.02 [0.90–1.16]

Progression free survival defined as the time from randomization until first progression or death from any cause, or the last follow-up for surviving patients without progression:

Overall HR (95% CI) earlier/shorter RT versus later/longer RT: 0.92 [0.83;1.02], P = 0.12;

Similar CT compliance between arms: 0.81 [0.71;0.92];

Different CT compliance between arms: 1.12 [0.95;1.31].

Toxicity: OR earlier/shorter RT versus later/longer RT:

Neutrophil: 1.54; 95%CI: 1.19-2.00; p=0.001;

Haemoglobin: 1.17; 95%CI: 0.91-1.52; p=0.22;

Platelets: 122; 95%CI: 0.96-1.55; p=0.11;

Oesophageal: 1.93; 95%CI: 1.45-2.56; p<0.001;

Pulmonary: 1.50; 95%CI: 0.86-2.62; p=0.16;

Cardiac: 3.12; 95%CI: 1.46-6.68; p=0.003.

Earlier or shorter’ delivery of thoracic radiotherapy with planned CT significantly improves 5-year overall survival at the expense of more acute toxicity, especially oesophagitis.

Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question

Level of evidence: GRADE (per comparison and outcome measure) including reasons for down/upgrading

Sensitivity analyses (excluding small studies; excluding studies with short follow-up; excluding low quality studies; relevant subgroup-analyses); mention only analyses which are of potential importance to the research question

Heterogeneity: clinical and statistical heterogeneity; explained versus unexplained (subgroupanalysis)

Lu, 2014

SR and meta-analysis of randomized controlled trials

Literature search from 1966 up to 2014

A: Skarlos, 2001

B: Park, 2012

C: Jeremic, 1997

Study design:

A: phase II randomized comparison of early vs. late hyperfractionated TRT concurrently with EC chemotherapy in LD SCLC

B: phase III trial of concurrent TRT with either the first or the third cycle of EP chemotherapy in order to determine the optimal timing of TRT for LD SCLC.

C: randomized comparison of initial vs. delayed AHTRT concurrently with EP chemotherapy for LD SCLC

Setting and Country: China,

Source of funding:

This study was funded by Project 81202806 supported by the National Natural Science Foundation of China and the Zhejiang Province Medical Science Fund Project of China (grant nos. 2012KYB034 and 2012RCB004).

Inclusion criteria SR: randomized controlled clinical trials that compared early to late concurrent TRT, fully published in journals and relevant scientific meetings, for which full details were available. The patients were required to have histologi- cally and cytologically confirmed LD SCLC.Radiotherapy was administered concurrently with chemotherapy and the chemo-therapeutic regimen was EP̸EC.

3 RCTs included

Important patient characteristics at baseline:

N, mean age I/C

A: 86; 61/60

B: 222; 60/61

C: 107; 59/59

Groups comparable at baseline?

Early concurrent thoracic radiotherapy with etoposide and cisplatin/carboplatin chemotherapy: within 30 days after chemotherapy initiation.

A: Etoposide combined with carboplatin (EC) + 45 Gy (1.5 x 2 daily x 15); PCI only if complete response

B: Etoposide combined with cisplatin (EP) + 52.5 Gy/25 fx (2.1, once daily); PCI when complete or partial response

C: Etoposide combined with cisplatin (EP) + 54 Gy (1.5 x 2 daily x 18); PCI when complete or partial response

Late concurrent thoracic radiotherapy with etoposide and cisplatin/carboplatin chemotherapy: after 30 days following the initiation of chemotherapy.

A: Etoposide combined with carboplatin (EC) + 45 Gy (1.5 x 2 daily x 15); PCI only if complete response

B: Etoposide combined with cisplatin (EP) + 52.5 Gy/25 fx (2.1, once daily); PCI when complete or partial response

C: Etoposide combined with cisplatin (EP) + 54 Gy (1.5 x 2 daily x 18); PCI when complete or partial response

End-point of follow-up: NR

For how many participants were no complete outcome data available? (intervention/ control): NR

Objective response rate:

There were no significant differences in the objective response between early and late concurrent TRT (RR=1.01, 95% CI: 0.86-1.18, P=0.90)

1-, 2-, 3-, 5-year survival rates between early versus late RT with chemotherapy:

RR=1.06, 95% CI: 0.88-1.27, P=0.56;

OR=1.15, 95% CI: 0.77-1.71, P=0.49;

RR=0.90, 95% CI: 0.66-1.22, P=0.49; and

OR=1.18, 95% CI: 0.64-2.16, P=0.60

Toxicity:

The total incidence of grade 3-4 adverse events, including anemia, leukopenia, neutropenia, thrombocytopenia, nausea and vomiting, infection, esophageal toxicity, pulmonary toxicity, alopecia and hemorrhage with early concurrent TRT was significantly higher compared to that with late concurrent TRT (RR=1.21, 95% CI: 1.03-1.43, P=0.02).

In conclusion, we demonstrated that late concurrent TRT with EP/EC chemotherapy is suitable for LD SCLC patients, particularly elderly patients or those with bulky tumors. However, further studies on concurrent TRT with EP̸EC chemotherapy for LD SCLC are required in order to increase overall survival rates and decrease treatment-related toxicity.

In research objectives is mentioned that overall survival the primary objective of the study is, but there are no results given on overall survival.

Besides, the definition of the objective response to the different treatment arms is not given. It is therefore not clear what this beholds.

It is not clear whether only RR or sometimes OR is calculated for the 1-, 2-, 3-, 5-years survival: discrepancy is noted between the results section and forest plots.

Study

First author, year

Appropriate and clearly focused question?

Yes/no/unclear

Comprehensive and systematic literature search?

Yes/no/unclear

Description of included and excluded studies?

Yes/no/unclear

Description of relevant characteristics of included studies?

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?

Yes/no/unclear

Potential risk of publication bias taken into account?

Yes/no/unclear

Potential conflicts of interest reported?

Yes/no/unclear

De Ruysscher, 2016

Yes

Yes

Yes

Yes

NA

No

Yes

Yes

Yes, for the SR, not for individual studies

Lu, 2014

Yes

Yes

No

No

NA

No

Unclear

Unclear, overall surival not mentioned and not clear what objective respons means

No