A current review of dose-escalated radiotherapy in locally advanced non-small cell lung cancer

Machtay et al. conducted a retrospective analysis of 1356 LANSCLC patients from seven prospective clinical trials of the Radiation Therapy Oncology Group (RTOG).2 Biologically equivalent dose (BED) and time-adjusted BED were calculated for each patient. The study revealed that BED was highly correlated with OS and loco-regional relapse-free survival (p < 0.0001). Increase of 1 Gy in BED was related with a 3% (HR = 0.97) improvement in local control and a 4% (HR = 0.96) relative improvement in survival. It is noteworthy that accompanied with escalated dose, treatment related-toxicity may be increased. In several randomized trials, a median survival of 15–20.6 months was observed in LANSCLC patients treated with a radiation dose of 60–66 Gy and concurrent chemotherapy.3, 4, 5, 6, 7, 8 A serial phase I and II trials explored the efficacy of dose escalation to 74 Gy radiotherapy concurrent with chemotherapy and showed an improved median OS of 21.6–37 months with acceptable toxicity.9, 10, 11, 12 Motivated by these results, RTOG launched a large randomized phase III study 0617, trying to find out whether a 74 Gy radiotherapy was superior to a 60 Gy radiotherapy administered with concurrent chemotherapy followed by consolidative chemotherapy. The result suggested that compared with 60 Gy radiotherapy, neither overall survival nor local control improved in high-dose radiotherapy arm (median OS time: 28.7 vs. 20.3 months, p = 0.004; 2-year local failure rate: 30.7% vs. 38.6%, p = 0.13).13 The prolongation of overall treatment time (7.5 weeks) and the associated tumor repopulation may be the contributing factors to this unsatisfactory outcome.14 Radiobiology and clinical trials have confirmed that the doubling time of most tumors is less than one week.15, 16 Dose escalation by simply increasing fraction numbers results in lengthened overall treatment, which has proven to have a negative impact on tumor control. Worse overall survival was observed when the treatment course exceeded 6 weeks.17, 18 In addition, results of RTOG 0617 showed that the exposure of lung, esophagus, and heart were significantly higher in high-dose radiotherapy arm; greater toxicity may be another possible explanation.13, 14 Brower et al. analyzed 33566 patients with stage III NSCLC who underwent concurrent chemoradiation and found that dose escalation above 60 Gy was associated with improved OS.19 But an OS plateau was also found when radiation dose prescribed was greater than 70 Gy. It is suggested that dose escalation should be limited in a specified range.

Recent meta-analysis demonstrated a survival benefit of dose escalation in patients treated with sequential chemoradiotherapy. However, in concurrent chemoradiotherapy group, increased dose was related to poorer survival.20, 21 One possible explanation is that the underlying toxicity accompanied with concurrent chemoradiotherapy compromises the survival benefits of dose escalation in tumor control.

Therefore, in the era of concurrent chemotherapy, applying traditional approaches of dose escalation in unselected patients could lead to extra toxicity and impaired survival. There is a need to explore safe, efficacious and feasible dose escalation methods for LANSCLC.

Fixed dose radiotherapy has been long used in dose dose-escalation studies. However, with varied tumor volumes, the tolerance of normal tissue would be different and dose delivery could be personalized accordingly. Several recent studies explored the feasibility of personalized radiotherapy. The phase II trial of van Baardwijk et al. evaluated dose intensification based on normal tissues concurrent with chemotherapy for patients with LANSCLC.36 After completing concurrent chemoradiotherapy to 45 Gy in 1.5 Gy bid fractions, boost dose was escalated 2 Gy per fraction in daily increments until reaching the limit dose of organ at risk (OARs). A total of 137 patients were included, 27% of them received a maximal allowed dose of 69 Gy. The median radiotherapy dose was 65 Gy. They reported a 2-year OS rate of 52.4% and an acceptable adverse effects (G3 esophagitis: 30.1%, ≥ G3 pneumonitis: 3%).

Selective dose escalation according to tumor activity and radiosensitivity has also been tested. High fludeoxyglucose (FDG) uptake prior to treatment has been demonstrated as a negative indicator for local recurrence.37 Based on this, a phase II randomized clinical trial evaluated the role of dose escalation in high FDG uptake area. Patients who completed an initial radiotherapy of 66 Gy in 24 fractions were then assigned either to receive a boost in the entire primary tumor (group A) or in the high FDG uptake area (> 50% maximum standardized uptake values (SUVmax) (group B). Similar with the previous study, maximal boost dose was delivered within the constraints of normal tissue. The results showed that average doses of primary tumors in groups A and B were 77.3 ± 7.9 Gy and 77.5 ± 10.1 Gy, respectively. For group B, the average dose in boost area reached 86.9 ± 14.9 Gy. Organs in the mediastinum were thought to be the major dose-limiting organs, such as great vessels, trachea etc. However, the local control and survival data was not provided.38 The existence of hypoxia is strongly associated with radioresistance and unfavorable prognosis.39 Vera et al. carried out a prospective phase II clinical trial to investigate the efficacy of selectively dose increase in hypoxic zones.40 18F-misonidazole (18F-FMISO) PET-CT was used to detect hypoxic areas and to guide the delineation of boost volumes. Boost dose was prescribed as high as possible within the tolerated dose of lung and spinal cord. A total of 54 LANSCLC patients treated with concurrent chemoradiotherapy were enrolled and 34 patients were 18F-FMISO positive, of whom, 24 had a dose escalation up to 86 Gy, 10 received a standard radiotherapy of 66 Gy. In 18F-FMISO positive patients, dose escalation showed no improvement in progression-free survival and OS. It suggests that with dose of hypoxic region escalated up to 86 Gy, the survival still cannot be improved.

Dynamic changes in tumor volume during radiotherapy lead to the idea of adaptive radiotherapy. Kong et al. 41 found that tumor volume was significantly shrunk when radiation dose reached 45 Gy, which offers opportunity to adapt target area in the middle of treatment. The reduction in target volume allows delivering higher radiotherapy dose. They then conducted a Phase II clinical trial to test the efficiency of adapting target volume based on midtreatment PET-CT. Forty-two inoperable patients with stage I–III NSCLC were analyzed. Patients had their target volume re-planned according to midtreatment PET-CT and received a maximally escalated dose without increasing radiation induced lung toxicity. The median dose was 83 Gy. They provided a promising 2-year LRC approximately 62%.42 The randomized RTOG 1106 trial (NCT01507428) is currently ongoing attempting to verify this finding. The control group was designed to give 60 Gy in 30 fractions. In the adaptive group, the target was redefined on the mid-treatment PET-CT after an initial 46.2 Gy in 21 fractions delivered. An individualized escalated dose ranged from 19.8–34.2 Gy/9 fractions with a total dose up to 80.4 Gy. This result would offer us more information.

Furthermore, individualized radiotherapy based on molecular biological information (sensitivity and risk of injury) has also been investigated. Recently, Scott et al. proposed a genome-based model to identify tumor radiosensitivity, genomic-adjusted radiotherapy dose (GARD), which was calculated by gene-expression-based radiosensitivity index and the linear quadratic model.34 Lower tumor GARD score predicts radiation resistance, thus higher radiation doses could be administered. The analysis confirmed that GARD was highest in head and neck cancers and cervical cancers, while the lowest in gliomas, which could be used to guide individualized escalated dose prescription. Another novel idea proposed by MD Anderson Cancer Center is that escalated tumor dose could be delivered according to the risk of radiation pneumonitis estimated by dose-volume histograms and single-nucleotide polymorphism information.44 Although the above studies are not yet mature enough to guide clinical practice, it may be a development trend in the future.

A lesson from RTOG 0617 is that normal tissue exposure should be fully considered while escalating doses. Previous studies have shown that protons and heavy ions have unique characteristic known as Bragg peak, which offers the possibility to increase tumor dose while sparing normal tissues.45, 46

Higgins et al. retrospectively analyzed 243,822 patients with stage I- IV NSCLC in the National Cancer Database; 243,474 of them were treated with photon radiotherapy and 348 were treated with proton radiotherapy.47 The analysis indicates that low-income groups tend to choose non-proton therapy (p < 0.011). After propensity matching analysis, a significant superior 5-year survival rate of stage II–III patients was found in the proton therapy group (23.1% vs. 13.5%; p<0.01). The prospective single-arm phase II clinical trial conducted by Chung et al. also confirmed the safety and efficacy of proton radiotherapy.48 A total of 64 patients with stage III NSCLC were enrolled in the trial; all patients received 74 Gy (relative biologic equivalent, RBE) proton radiotherapy combined with concurrent chemotherapy. They reported a median OS of 26.5 months. The incidence of grade 3 or greater toxicity including esophagitis and radiation pneumonitis was 8% and 14%, respectively. Contradicts to these findings, the more recent results of phase II randomized trials published by Liao et al. failed to show the superiority of proton radiotherapy.49 This trial compared the local control and toxicity of intensity modulated radiation therapy (IMRT) and proton radiotherapy of 66–74 Gy (RBE) combined with concurrent chemotherapy in NSCLC patients. Although there was no significant difference in the incidence of radiation pneumonitis (p = 0.40) and local control (p = 0.86) in both groups, proton radiotherapy significantly reduced heart exposure (p = 0.002). However, OS was not the endpoint for this study, the effect of reduced heart dose on OS is still unknown. The ongoing Phase III prospective clinical trial RTOG 1308 (NCT01993810) which compares the OS between proton radiotherapy and IMRT may bring some insight into this issue. Patients with inoperable stage II–III NSCLC were randomized to proton radiotherapy versus IMRT photon arm. Patients in the proton radiotherapy arm received 2 Gy (RBE) daily to 70 Gy (RBE) course, whereas, those patients on the IMRT arm received 2 Gy to 60 Gy course, concurrent with weekly platinum-based chemotherapy followed by 2 cycles of consolidation chemotherapy.

Heavy ion beams possess the physical advantages of proton beams, also better biological effects, which seemed to be more suitable for dose escalation studies. Takahashi et al. performed phase I/II non-randomized prospective clinical study to test carbon ion radiotherapy in LANSCLC.50 Phase I trial included a total of 36 patients with escalated dose from 68 Gy (RBE) to 76 Gy (RBE) in 16 fractions. The MTD was 76 Gy (RBE) with 2 patients developed G3 toxicity including pneumonitis and tracheo-esophageal fistula. In the phase II trial, 22 patients were analyzed; all of them received a regimen of 72 Gy (RBE) in 16 fractions. No grade 3 or higher toxicity was found. The 2-year LRC and OS of 72 patients were 93.1% and 51.9%, respectively. This outcome data are in keeping with the multicenter retrospective analysis reported by Karube et al. 51 The median dose prescribed for 64 stage II–III NSCLC patients was 72 Gy (RBE) in 16 fractions. The 2-year LRC and OS rate were 81.8% and 62.2%, respectively. No grade 2 or greater toxicity occurred. Shirai et al. conducted a retrospective analysis of 23 patients with T2b–4N0M0 stage NSCLC treated with carbon ion radiotherapy. 52 Sixty-five percent of patients received a total dose of 52.8–60 Gy (RBE) in 4 fractions and 35% of patients were treated with 64–70.5 Gy (RBE) in 16 fractions. The 2-year LRC and OS rates were 81% and 70%, respectively, and no person experienced ≥ 2 degree radiation pneumonitis. The above studies showed that hypofractionation carbon ion radiotherapy could be safely and efficiently used in LANSCLC. However, the conclusion still needs to be validated by larger prospective studies. Combined modality such as chemotherapy and immunotherapy could be further explored. In addition, cost-effectiveness of proton and heavy ion radiotherapy should also be considered.