Dose and Fractionation in Radiation Therapy of Curative Intent for Non-Small Cell Lung Cancer: Meta-Analysis of Randomized Trials

Purpose The optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy. Methods and Materials Eligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled. Results 3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, higher versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P<.001), average age at randomization (P<.001), and year trial started (P for trend=.004), but not for proportion of patients with squamous cell carcinoma (P=.2). Conclusions In trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiation therapy was given without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival, and no upper dose level was found above which there was no further benefit. These findings support the consideration of further radiation therapy dose escalation trials, making use of modern treatment methods to reduce toxicity.


Introduction
Lung cancer is the most common cause of cancer death worldwide, and survival has improved little since the mid-1970s, with 10-year survival at only 4% in 2011 (1,2). Almost 90% of lung cancers are non-small cell (NSCLC) (3), and surgery is the main curative treatment. Many patients are, however, inoperable at presentation (4), and for them, radiation therapy of curative intent may be considered, possibly in conjunction with chemotherapy. Since the 1970s, conventional radiation therapy in NSCLC has been defined as 60 to 63 Gy in 1.8-to 2.0-Gy fractions (5-7), but several trials have considered alternatives. These include splitcourse radiation therapy (with a several-day break), hyperfractionation (multiple smaller daily doses), hypofractionation (fewer, larger-dose fractions), acceleration (delivering the same dose over a shorter period), or changing total dose while keeping the same dose per fraction. Changes to these parameters all affect the biologically effective dose (BED) and may alter tumor control probability.
No randomized trials of radiation therapy dose and fractionation in NSCLC have included more than 600 patients, and many include fewer than 200. Consequently, most have not, individually, had sufficient power to detect modest effects on survival that would be important clinically. Where significant effects have been seen in individual trials, they may reflect extremes in the play of chance. More powerful inferences can be obtained when the data from all trials addressing a particular question are combined in a meta-analysis. Several meta-analyses of trials comparing different radiation therapy regimens in NSCLC have been conducted (8)(9)(10), but none has evaluated the effect of radiation therapy in terms of different levels of BED, and none has included all the relevant trials.
Several randomized trials have addressed the role of chemotherapy in addition to radiation therapy in NSCLC (11,12). A Cochrane review of 3752 patients in 25 trials concluded that concurrent chemoradiation therapy resulted in better survival than radiation therapy alone (hazard ratio [HR], chemotherapy vs not: HR 0.71, 95% CI 0.64-0.80) or radiation therapy with sequential chemotherapy (HR 0.74, 95% CI 0.62-0.89) (13). Therefore, over the past decade, this has become the standard of care for patients with locally advanced NSCLC. However, patients treated with chemoradiation therapy experience more toxicity than do those treated with radiation therapy alone, particularly when chemotherapy is given concurrently (7,13). Thus, within the context of chemoradiation, radiation dose escalation may result in a level of toxicity that outweighs any benefit from improved tumor control.
Given the ongoing uncertainty regarding the optimal dose for curative-intent radiation therapy for NSCLC, and the high levels of toxicity, it is not surprising that radiation therapy practice varies (12,14,15). Recent advances are, however, enabling radiation therapy to be delivered with lower toxicity than previously, so knowledge regarding the optimal dose for curative-intent radiation therapy is becoming more important. We have, therefore, conducted a meta-analysis of published data from randomized trials comparing different radiation therapy regimens. Our aim was to examine whether radiation therapy regimens delivering a higher corrected dose increased the overall survival in curative-intent radiation therapy for NSCLC, either when given alone or with chemotherapy.

Methods and Materials
Literature search and selection criteria The Embase database was searched, using variations of the terms radiation therapy dose fractionation, hyperfractionation, hypofractionation, accelerated radiation therapy, and lung cancer ( Fig. E1; available online at www .redjournal.org). Studies starting between 1980 and April 28, 2015, were eligible if they included a randomized comparison of 2 or more external beam radiation therapy dose fractionation regimens, with other treatments identical in any arms compared. A trial using hospital numbers to randomize was excluded (16). EQD2TZ BED 1 þ 2 a=b where a/b was assumed to be 10 and BED was defined as where NZnumber of fractions; d Z dose per fraction; k Z biologic dose needed to compensate for repopulation, which was assumed to be 0.6 Gy; T Z total treatment time in days; and T delay Z time until onset of repopulation, assumed to be 21 days. For regimens lasting less than 21 days, k was set to zero (17).

Statistical analyses
Analyses were based on median survival times (18), extracted from trial publications for each arm. If not reported, they were derived from survivor function graphs or 1-year survival. For each randomized comparison, a median survival ratio was calculated by dividing median survival in the higher-dose arm by median survival in the lower-dose arm. For trials with more than 2 study arms, separate median survival ratios compared with the lowest-dose arm were calculated for every other trial arm, resulting in separate treatment comparisons. Confidence intervals and significance tests were based on standard errors (19). All analyses were conducted in Stata version 13.0 (20). Further methodologic details are in Figure E2 (available online at www.redjournal.org).

Effect of chemotherapy on dose escalation
The median overall survival ratio, higher versus lower EQD2T, pooled across all randomized dose comparisons, was 1.07 (95% CI 1.00-1.15, PZ.05) (Fig. 2). When these comparisons were grouped according to whether the protocol specified no chemotherapy, sequential chemotherapy, or concurrent chemotherapy the heterogeneity between these groups was highly significant (PZ.001). The median survival ratios were 1.13 (95% CI 1.04-1.22, PZ.002) For randomized comparisons that included concurrent chemotherapy, there was no significant heterogeneity between the median survival ratios (PZ.5), nor was there any trend with increasing EQD2T difference between arms (PZ.1). There were only 2 randomized comparisons with sequential chemotherapy, including 193 patients, so the confidence intervals were wide.
When the 18 radiation therapyeonly comparisons were grouped according to dose in the lower-dose arm into 3 approximately equal-sized groups (Fig. 3B), the median survival ratio, higher versus lower dose, was 1.01 (95% CI 0.89-1.14, PZ.9) for comparisons where the EQD2T in the lower-dose arm was <49.5 Gy, whereas for comparisons in which it was 49.5 to 53.4 Gy, the median survival ratio was 1.17 (95% CI 1.02-1.33, PZ.02), and for comparisons in which it was !53.5 Gy, it was 1.28 (95% CI 1.10-1.49, P<.002). So, surprisingly, the median survival ratio increased progressively with increasing EQD2T in the lower-dose arm, with an increasing trend across the 3 groups (P for trendZ.01). Even for trials with EQD2T !53.5 Gy in the lower-dose arm, further dose escalation provided an additional improvement in survival. For the 5 trials in which the dose in the lower-dose arm was EQD2T !53.5 Gy and where the dose difference was EQD2T >10 Gy, the median survival ratio was 1.87 (95% CI 1.47-2.38, P<.001). When comparisons with EQD2T !53.5 Gy in the lower-dose arm were categorized into trials in which hyperfractionation was used to escalate dose versus other trials, the median survival ratio for the 2 groups was similar (1.27, 95% CI 1.08-1.51, and 1.32, 95% CI 0.92-1.89, P for differenceZ.9) (Fig. 4B).

Heterogeneity between trials and exploratory analyses
The median survival ratios for the 18 radiation therapyeonly dose comparisons varied substantially, from 0.68 (95% CI 0.47-0.99) to 2.28 (95% CI 1.42-3.67) (P for heterogeneity<.001) (Fig. 2). The difference in EQD2T between trial arms did not account for all the excess heterogeneity, so exploratory analyses were conducted to examine the associations between median survival ratios and other available factors (Fig. 5). The median survival ratio, higher versus lower EQD2T, was higher for trials conducted in China than for trials conducted elsewhere  (Fig. 5C). By contrast, when the trials were grouped according to whether most patients had squamous cell carcinoma (SCC), no significant difference was found (PZ.2) (Fig. 5D). Geographic region, age, and year trial started were correlated, whereas percentage of patients with SCC was not highly correlated with any other factor (Table E3; available online at www.redjournal.org). An analysis adjusting for all 4 factors showed the strongest association between geographic region and median survival ratio (PZ.008), with all other factors statistically nonsignificant (Table E4; available online at www.redjournal.org).

Discussion
This large meta-analysis including 3795 patients in 25 treatment comparisons has, for the first time, brought together all post-1980 randomized evidence comparing different curative-intent radiation therapy regimens in NSCLC. To eliminate the confounding effects of other treatments, we considered only trials in which other protocol treatments were identical in both arms. We focused on median survival ratios in relation to corrected dose (ie, time-corrected equivalent dose, EQD2T) differences between trial arms and whether the radiation therapy was given alone or with chemotherapy.

Radiation therapy without chemotherapy
In 18 trials where no protocol chemotherapy was administered, radiation therapy dose escalation improved overall survival (median survival ratio: 1.13, 95% CI 1.04-1.22), corresponding to a survival gain of approximately 2 months for patients in these trials. The survival improvement increased progressively as the difference between EQD2T in the 2 trial arms increased and, in trials where the difference was EQD2T >10 Gy, the median survival ratio was 1.47 (95% CI 1.23-1.75). Remarkably, even for trials where the dose in the lower-dose arm was high (EQD2T !53.5 Gy), further dose escalation provided an additional improvement in survival (median survival ratio: 1.28, 95% CI 1.10-1.49) (Fig. 3B). In trials with EQD2T !53.5 Gy in the lower-dose arm where the dose difference exceeded EQD2T 10 Gy, the median survival ratio was 1.87 (95% CI 1.47-2.38), and for these patients the survival gain was approximately 1 year.
The commonest method of altering dose and fractionation in these trials was hyperfractionation. Two previous meta-analyses of different radiation therapy regimens focused on comparing hyperfractionation or acceleration with conventional radiation, rather than on corrected dose   All trials in ll trials in ii ii)

All trials in ii)
Within-group heterogeneity: X 2 = 2.0 on 2 df, P=.4   (8,10). In our study, dose escalation of EQD2T >10 Gy showed a similar improvement in survival regardless of whether it was achieved by hyperfractionation or by other means, suggesting that dose escalation may improve survival regardless of the method used. Survival improvement from radiation therapy dose escalation was associated with 3 other factors: younger age, recent trial start date, and whether the trial was conducted in China. The strongest association was for trials conducted in China. Nothing in the trial publications indicated that the Chinese trials differed systematically from other trials, and inasmuch as the 3 factors were highly correlated, the geographic association may not be causal. By contrast, it would not be surprising if radiation therapy dose escalation had a greater benefit in younger patients, who may be better able to tolerate radiation therapy than older patients, and All trials in ll trials in i) i)

All trials in ll trials in ii)
ii) ) Other trials Other trials ii) ) Other trials Other trials 13 72 Gy in 40 (WE) 2 Gy in 40 (WE) vs vs 72 Gy in 40 72 Gy in 40

All trials in ll trials in i) + ) + ii ii)
Heterogeneity between eterogeneity between i) and and ii): X ): X 2 = 0.03 on 1 df, P=.9 = 0.03 on 1 df, P=.9 All trials in ll trials in i) + ) + ii ii)

Dose and fractionation, ose and fractionation, higher vs lower trial arms higher vs lower trial arms A Geographical region A Geographical region i) ) Trial conducted in China Trial conducted in China
ii) ) Trial conducted elsewhere Trial conducted elsewhere

All trials ll trials
All trials i ll trials in ii ii)     thus may receive the full prescribed dose. Younger patients may also face a lower risk of death resulting from toxicity than older patients, and have lower competing risks of death from other causes. Survival improvement was also greater in more recent trials. This could be due in part to increased prescribed tumor doses and improved radiation therapy techniques. There was no significant association between dose escalation and the percentage of patients with SCC, but for most trials, the percentage of patients with SCC was between 40% and 60%, so there was little variation in this factor.

Radiation therapy with chemotherapy
In trials with concurrent chemotherapy, higher EQD2T led to poorer overall survival, suggesting that the risks of increasing radiation therapy dose outweigh the benefits when concurrent chemotherapy is given (Fig. 2)

Radiation therapy, chemotherapy, and toxicity
The probability of sterilizing a tumor increases with increasing tumor radiation dose (42). However, lung cancer radiation therapy inevitably delivers dose to normal lung and adjacent organs that may cause pneumonitis, esophagitis, heart disease, and lung fibrosis (43)(44)(45). Adding chemotherapy to radiation therapy further increases toxicity, including myelosuppression, esophagitis (up to 6 times higher with concurrent chemotherapy), pneumonitis, and treatment-related death (46). Increasing the irradiated volume alongside concurrent chemotherapy can also increase toxicity (47). Toxicity is thus a primary constraint in increasing radiation and chemotherapy dose in NSCLC treatment, especially because patients often have multiple comorbidities. In this study, it was not possible to analyze the effects of toxicity on median survival because of the variability in toxicity reporting across trials in terms of type, severity, and time point.
Modern radiation techniques are being developed to reduce toxicity. They include intensity modulated radiation therapy, proton beam therapy, and personalized isotoxic radiation therapy, in which patients receive maximal radiation therapy dose based on normal tissue constraints and their individual tumor size and location (48). In future, these efforts to reduce toxicity may facilitate radiation therapy dose escalation, even when chemotherapy is also given.

Strengths and limitations
Our meta-analysis has several strengths. It is larger and has more power than previously published meta-analyses of trials of curative-intent radiation therapy for lung cancer (8)(9)(10). We have, for the first time, examined trials both according to the corrected radiation therapy dose and to whether chemotherapy was delivered. Most importantly, we have included total treatment time in our dose calculation (EQD2T rather than EQD2). Omitting the time factor would have resulted in substantially different results because it would have reversed the higher and lower dose arms for 7 trials (numbers 2, 6, 7, 9, 10, 17, and 18), and for 2 further trials (numbers 13 and 15) the corrected doses would have been identical in the 2 arms. This is because in 7 of these trials, 1 of the arms was hyperfractionated (more dose intense) whereas the other was conventionally fractionated.
The main limitation of our study is a lack of individual patient data. Effects seen at the aggregate level may be weaker or stronger than those examined at the individual level. This also prevented us from considering survival at 2 years, by which time most patients with occult distant metastases when irradiated would have died. We also could not conduct analyses of deaths resulting from lung cancer versus other causes. Another limitation is that the calculation of EQD2T involves radiobiologic assumptions about the way in which radiation kills tumor cells, including values of parameters. For example, in the CHART trial (number 2), 67% of patients in the higher-dose arm versus 34% in the lower-dose arm experienced severe esophagitis, although the EQD2T difference to the tumor was calculated to be only 2.1 Gy (49).

Conclusions
In conclusion, survival in locally advanced NSCLC patients has seen little improvement over 40 years (2), so any evidence of improvement in survival is clinically important. Our study shows that when radiation therapy is given without chemotherapy, escalating radiation therapy dose leads to improved survival. This suggests that the optimal radiation dose has yet to be reached, and it provides support for further trials of dose escalation, especially with modern radiation therapy techniques that lower toxicity. When chemotherapy is given with radiation therapy, the ability to achieve a cure has, until now, been limited by toxicity, especially when it is given concurrently. Therefore, it may be that the optimal radiation dose for chemoradiation therapy has also not yet been reached in the context of new advances, such as personalized isotoxic dose escalation, and in the continued search for the optimal concurrent chemotherapy regimen. Our study therefore also provides support for consideration of further trials in radiation dose escalation of chemoradiation therapy for locally advanced NSCLC.