Skip to main content

Advertisement

Accelerated hypofractionated radiotherapy plus chemotherapy for inoperable locally advanced non-small-cell lung cancer: final results of a prospective phase-II trial with a long-term follow-up

Article metrics

Abstract

Background

Concurrent chemotherapy and radiation using conventional fractionation is the standard treatment for inoperable, locally advanced non-small-cell lung cancer (NSCLC). We tested accelerated hypofractionated radiotherapy (AHR) and chemotherapy for the treatment of locally advanced NSCLC.

Methods

Eligible patients with locally advanced NSCLC were treated with induction chemotherapy (cisplatin and docetaxel), followed by AHR using tomotherapy and consolidation chemotherapy. The prescribed doses were 30 Gy/5 daily fractions at the reference isodose (60–70%) to the tumor, and 25 Gy/5 daily fractions to the clinically involved lymph nodes. The primary end-point was response rate (RR); the secondary end-points were acute and late side-effects, local progression-free survival (PFS), metastasis-free survival (MFS) and overall survival (OS). This trial closed before the first planned interim analysis due to poor accrual.

Results

From January 2009 to January 2012, 17 of the 23 enrolled patients were evaluable. Treatment yielded an overall RR of 82%. Median follow-up was 87 months (range: 6–87), local PFS was 19.8 months (95% CI 9.7 - not reached), MFS was 9.7 months (95% CI 5.8–46.0) and OS was 23 months (95% CI 8.4–48.4). 70% of patients experienced acute G4 neutropenia, 24% G4 leukopenia, 24% G3 paresthesia, 4% G3 cardiac arrythmia, 4% underwent death after chemotherapy. Late toxicity was represented by 24% dyspnea G3.

Conclusions

AHR combined with chemotherapy is feasible with no severe side-effects, and it appears highly acceptable by patients.

Trial registration

This study is registered with the EudractCT registration 2008-006525-14. Registered on 9 December 2008.

Introduction

Non-small-cell lung cancer (NSCLC) represents the most common cause of death from cancer worldwide, in particular in Europe and the USA [1]. Tobacco use is the main risk factor for lung cancer, with a high rate of other pulmonary tumors related to the effects of smoking [2].

The majority of patients present with locally advanced or metastatic disease at diagnosis [3]. In this setting, chemotherapy and concomitant radiotherapy represent the gold standard treatment. Some studies [4, 5] have compared sequential with concomitant chemoradiotherapy with conventional fractionation showing the superiority of the latter, although with a higher rate of acute and chronic side-effects. However, poor long-term results are distinctive of concomitant chemoradiotherapy in the treatment of locally advanced NSCLC.

The integration of chemotherapy and radiotherapy has posed many problems about potential side-effects. Radiotherapy has shown better effectiveness in locoregional control on increased dose [6], as pointed out by the Radiation Therapy Oncology Group (RTOG) 73–01 landmark trial [7]. However, some dose escalation trials have reported that a higher locoregional control is not correlated to survival benefits, except for the cut-off of 60 Gy with 3-dimensional conformal radiotherapy (3D-CRT) [8,9,10]. RTOG 0617, compared 60 Gy vs. 74 Gy both with chemotherapy (carboplatin and paclitaxel) and reported a median survival of 29 months in patients receiving 60 Gy versus 20 months in patients receiving 74 Gy. Furthermore, the 74 Gy arm showed an increased risk of death leading to an early closure of the trial [11].

Attempts to increase the total dose of conventional treatments and the use of hyperfractionated treatment have yielded no substantial difference from previous experiences. Arimoto et al. [12] observed interesting efficacy results in early-stage peripheral lung tumor using accelerated hypofractionated radiotherapy (AHR). Polico et al. [13] reported that AHR is efficacious, feasible and safe also for locally advanced disease, i.e. lung tumor and mediastinal nodes. The only possibility to improve treatment outcomes for locally advanced non small cell lung cancer is to increase local control and avoid metastatic spread.

The aim of our study was to increase local control through AHR and sequential chemotherapy for patients with locally advanced NSCLC. We analyzed RR and down-staging in NSCLC and involved mediastinal lymph nodes as primary endpoint. Secondary endpoints were acute and late side-effects, local progression-free survival (PFS), metastasis-free survival (MFS) and overall survival (OS).

Methods and materials

We conducted a prospective phase-II clinical trial enrolling cyto-histologically proven, locally advanced NSCLC patients. All patient characteristics are shown in Table 1.

Table 1 Patient characteristics: (y) years; (n) number

All patients were initially staged with a total body CT scan, integrated 18F-FDG PET-CT scan, fibroscopy (FBS) and trans-bronchial nodal aspiration (TBNA), endoscopic bronchial/esophageal ultrasound (EBUS and EUS) and guided fine needle aspiration (LN FNA) for mediastinal lymph nodes staging. Brain MRI was performed only in case of suspicious brain metastases from the head CT. Other inclusion criteria were: performance score (PS) 0–1, < 70 years of age, > 3 months of life expectancy, presence of one measurable lesion according to RECIST criteria 1.1, normal organ and bone marrow function, FEV 1 (forced expiratory volume in the first second) > 50% of its predicted normal value. Exclusion criteria were: small-cell lung cancer (SCLC) diagnosis, prior neuropathy with neurotoxicity ≥2 (NCI/CTC), obstructive pneumonia, bronchial fistula, prior chemotherapy, prior radiotherapy to the thorax, > 10% weight loss in the last 6 months, stage-IIIA (T3 N1 or N2 < 3 lymph nodes without extracapsular involvement) or stage-IIIB NSCLC with supraclavicular and scalenic lymph nodes involvement, pleural and pericardial effusion, documented esophageal involvement in the entire thickness, involvement of cardiac ventricles, vertebral foramen and/or spinal marrow according to TNM Cancer Staging 7th edition. Patients with other malignancies in the 5 years before entering the study, except cured basal cell carcinoma of the skin and cured in situ carcinoma of the uterine cervix, or any other morbidity contraindicated for chemotherapy (e.g. heart diseases, active infections) were ineligible. We discussed all these cases in our multidisciplinary meeting called: Gruppo interdisciplinare patologia oncologica (GIPO).

Patients received two courses of induction chemotherapy with cisplatin 75 mg/m2 and docetaxel 75 mg/m2 on day 1 every 21 days. After the second chemotherapy cycle, between days 15 and 19, patients underwent radiotherapy using helical tomotherapy (TomoTherapy Inc., Madison, WI, USA). After at least 15 days of radiotherapy, patients were administered two consolidation courses of chemotherapy with cisplatin 75 mg/m2 and docetaxel 60 mg/m2 on day 1 every 21 days (Fig. 1). The use of granulocyte-colony stimulating factor (G-CSF) was allowed for secondary neutropenic prophylaxis.

Fig. 1
figure1

Trial design. This flow chart describes the scheduled chemotherapy and radiotherapy (RT) treatment. All patients underwent Fibroscopy (FBS) with nodal biopsy 15 days after the end of RT. The radiological evaluation was performed 15 days after the end of the protocol and after the biopsy with Positron Emission Tomography/Computed Tomography (PET/CT)

To perform radiotherapy, patients were immobilized in the supine position with their arms overhead using a Posirest-2 (CIVCO) prior to CT simulation scan. All patients underwent a planned CT scan with contrast agent injection (Brilliance Big Bore CT Philips, Crowley, UK). The chest CT simulation scan was acquired from the middle neck to the upper abdomen at time points 0, 30, 60 and 180 s during patients’ free breathing in order to simulate the respiratory movement. All non-fused phases of the CT simulation scan were used to contour the gross tumor volume (GTV), the clinical target volume (CTV) and the organs at risk (OaR) for radiotherapy planning. GTV encompassed all known primary tumors and involved lymph node locations. Additional manual margins were applied for microscopic tumor (CTV) and lymph node extension following the respiratory movements observed in the multiphase CT simulation scan images to create a non-isotropic margin. Daily set-up errors were corrected using image guided radiotherapy (IGRT) with ConeBeamCT. Finally, the OaR were also delineated, i.e. the esophagus, heart, spinal cord (with a 0.3-mm safety margin extension), lungs, total lung, liver, stomach and body. The Pinnacle treatment planning system (version 9.3) was used for contouring. Contours were transferred onto a Hi-Art tomotherapy treatment planning station for inverse planning calculation.

A dose of 30 Gy/5 daily fractions at the reference isodose (60–70%) was prescribed to the CTV, with an increasing inhomogeneous dose within the tumor of up to 40 Gy to simulate brachytherapy dose distribution [14, 15]. A dose of 25 Gy/5 daily fractions at the reference isodose (60–70%) was prescribed to the lymph nodes CTV, with an increasing inhomogeneous dose of up to 37.5 Gy. We used a SBRT-like dose prescription to increase dose heterogeneity within the target (Fig. 2). The prescribed dose at 70% isodose allowed for the delivery of a high dose to the GTV, sparing as much normal lung tissue as possible. The OaR dose volume histograms (DVHs) were converted into a 2-Gy equivalent dose; we applied the dose constraints recommended by the literature data [16], while maintaining the OaR doses below the conventional fractionation values (Table 2a-b).

Fig. 2
figure2

Example of dose distribution in a patient with stage-IIIB pulmonary adenocarcinoma after 2 induction chemotherapy cycles. The color legend DVH in the column on the right illustrates the dose distribution. Prescription dose was 30 Gy/5 daily fractions with a heterogeneous dose escalation of up to 40 Gy inside the primary tumor to simulate brachytherapy dose distribution. Prescription dose was 25 Gy/5 daily fractions with a heterogeneous dose escalation of up to 37.5 Gy inside the nodal tumor. The different colors show the following isodoses: red, 30 Gy; deep blue, 40 Gy; aqua, 37.5 Gy; green, 25 Gy; purple, 20 Gy; light blue, 15 Gy; pink, 10 Gy; yellow, 5 Gy

Table 2 a, b Relevant normal tissue dosimetric parameters for organs at risk (OaR)

All treatments were performed using helical tomotherapy. Restaging procedures included integrated 18F-FDG PET-CT scan and EBUS/EUS FNA performed after at least 2 weeks of end of the protocol program. The mediastinal lymph node stations positive at staging were approached again with TBNA or FNA to confirm disease persistence or down-staging. After the end of the protocol, patients underwent a follow-up evaluation with a total body CT scan and laboratory examinations every 12 weeks. PET scan was performed in case of suspicion of disease progression.

The primary endpoint of the study was to determine the objective tumor response rate (RR) according to RECIST criteria 1.1. Secondary endpoints were acute and late side-effects, local progression-free survival (PFS), metastasis-free survival (MFS) and overall survival (OS).

This study was approved by the Ethics Committee IRST IRCCS AVR with approval number 331 05/11/2008, was also conducted in accordance with the Declaration of Helsinki and all patients signed the informed consent.

Statistical analysis

Objective RR [complete (CR) and partial response (PR)] was the primary endpoint of our study. The sample size was calculated using a minimax 2-stage Simon design. A 70% objective RR was considered acceptable for further testing of the experimental treatment, whereas a 50% objective RR was ruled out as futile. Using alpha and beta values of 0.05 and 0.20, respectively, at least 13 of the 29 patients were required to have obtained CR or PR in the first stage before moving on to the second stage. As an additional 14 patients were enrolled in the second stage, at least 24 of the total 43 patients were required to have reached CR or PR in the second stage for the combination to be considered sufficiently active to undergo further testing.

Unfortunately, after 36 months’ recruitment, the protocol committee decided to close the study due to a poor accrual rate, as only 17 evaluable patients had been enrolled. Despite the low statistical power of the study, the authors decided to present their results.

Acute and late toxicities were recorded according to NCI common terminology criteria for adverse events (CTCAE) version 3.0 [17] after patients had completed the protocol. In particular, dyspnea was measured according to patient-reported shortness of breath, grade of exertion, limitation of daily activities, as reported in CTCAE 3.0.

RR was evaluated as the proportion of patients experiencing reduction in tumor burden according to RECIST criteria 1.1. Progression-free survival (PFS) was calculated as the time from enrollment until disease progression or death, whichever came first. Local PFS (LPFS) was defined as the time during and after treatment with stable disease. Metastasis-free survival (MFS) was defined as the time from accrual to disease progression. OS was calculated according to the Kaplan-Meier method as the time from diagnosis until death or last recorded follow-up visit. All statistical analyses were performed using SAS Statistical software (version 9.3, SAS Institute Inc., Cary, NC, USA).

Results

From January 2009 to January 2012, 23 consecutive eligible patients were enrolled in the trial, of whom only 17 (74%) completed the protocol. In particular, of the 6 patients unable to complete the study, 2 had an allergic reaction to docetaxel and received a modified chemotherapy schedule, 1 developed tumor abscess complicated in lung infection after chemotherapy and received radiotherapy about 8 months later for local progression of disease, 1 underwent paroxysmal atrial fibrillation after the first course of chemotherapy, 1 died after induction chemotherapy for unspecified causes, and 1 developed G2 pulmonary hemorragie after induction chemotherapy.

Twenty-eight days (range 18–45) was the average time from the end of radiotherapy to the start of the third course of chemotherapy. Twenty-nine percent of patients received 75% of the planned dose of chemotherapy, whereas 47% of chemotherapy courses were administered using granulocyte-colony stimulating factor (G-CSF) as secondary neutropenic prophylaxis.

All patients completed the radiotherapy schedule. Table 2a-b collects the information about the OaR.

Acute grade (G) side-effects due to chemotherapy were G4 neutropenia (70%) and G4 leucopenia (24%), G3 paresthesie (24%), G3 lung infection (4%), whereas no severe acute side-effect was recorded during radiotherapy.

All side-effects are listed in Table 3. We analyzed the results of pulmonary function test and noticed that in the acute period there was a reduction in FEV1 and DLCO to a value of max 20 points related to a moderate ventilatory deficit and a value of max 28 points reduction related to a moderate capillary socket diffusion, respectively. As for late toxicity, we noticed that 13 patients had recovered from acute damage with normalization of FEV1 and DLCO values, whereas 4 patients who had experienced G3 pneumonitis had maintained their functional damage. Protocol-associated toxicity was particularly critical for chemotherapy. We reported 1 case of death after 1 cycle of chemotherapy induction for unspecified cause, and 5 cases of study drop-out due to induction chemotherapy toxicity.

Table 3 Acute and late toxicity

The treatment yielded radiologically and hystologically proven disease down-staging in 7 (41%) patients; the remaining 10 (59%) patients had stable disease. The 41% of patients experienced down-staging showed a longer OS of 86.7 months (95% CI 7.8-not reached) vs. 12.5 months (95% CI 6.2–27.1), a lower PFS of 6.2 months (95% CI 5.6–50.8) vs. 8.7 months (95% CI 5.3–10.1), and a lower MFS 6.2 of months (95% CI 5.6–50.8) vs. 9.7 months (95% CI 5.3-not reached) in patients who experienced stable disease.

Among the RR with down-staged patients, 18% reached CR, 65% had mediastinal lymph node down-staging with 70% N0, 18% N2 and 12% N3 persistent, and 41% obtained tumor shrinkage, as shown in Table 1. A 76% tumor RR was achieved according to RECIST criteria 1.1.

Forty-one percent of patients had tumor recurrence, of whom 23% in the same radiotherapy field and 18% outside the field, recorded during follow up time.

After a median follow-up of 87 months (range 6–87), median LPFS was 19.8 months (95% CI 9.7-not reached) and median MFS was 9.7 months (95% CI 5.8–46.0) with a median OS of 23 months (95% CI 8.4–48.4), as shown in Fig. 3a, b, c.

Fig. 3
figure3

a, b, c Overall survival (OS) (a), local progression-free survival (LPFS) (b), metastasis-free survival (MFS) (c). OS was calculated according to the Kaplan-Meier method as the time from diagnosis until death or last recorded follow-up. Pts = patients

Discussion

The novel approach of this protocol was the delivery of AHR to the tumor site and involved mediastinal lymph nodes. To our knowledge, this is the first protocol employing AHR with chemotherapy for the treatment of locally advanced NSCLC. The choice to combine accelerated hypofractionation radiotherapy and sequential chemotherapy instead of concomitant chemotherapy, was driven by the opportunity to avoid relevant acute toxicity. We used IMRT in tomotherapy and daily IGRT to deliver the treatment, in order to obtain disease down-staging and assess the efficacy of the proposed RT dosage schedule of 30 Gy/5 daily fractions to the primary tumor and the mediastinal nodes.

In Johnson et al.’s [18] phase-II trial, patients with locally advanced NSCLC were treated with induction chemotherapy with cisplatin and vinblastine, then evaluated for surgery or healing radiotherapy for a total dose of 54 Gy in 27 fractions: median OS was 12 months, and survival rates at 12, 24 and 36 months were 54, 39 and 11%, respectively. Furthermore, Perez et al. [19] published the final results of their study comparing different treatment schedules and the best results were obtained with daily bi-division, for a total dose of 69.6 Gy, with survival rates at 12 and 36 months of 58 and 20%, respectively. The combination of weekly paclitaxel, carboplatin and TRT (63 Gy) consolidation was also associated with optimal outcome but with important toxicity [20]. The RTOG 0617 study reported a median OS of 28.7 months for patients who received standard chemo-radiotherapy, which is higher than 23.0 months reported by our study. The reason for this could be traced to patient selection: in our study 88% of patients were staged IIIB, whereas only 34% of patients were staged IIIB in the RTOG 0617 study. The fact that IIIB-stage patients reported a worse prognosis than IIIA-stage patients may explain the difference in OS. Past studies obtained a similar OS rate to DART-bi, by exploiting the concept of dose differentiation (DART-bi) according to tumor size [21]. Moreover there are some retrospective studies about hypofractionation intensity modulated radiotherapy with similar patient selection, fractionation, range of prescribed dose, and technique, that report different OS data [22, 23]. Swanick et al. reported a retrospective analysis of patients with non-operable NSCLC (all stages) treated with IMRT-SIB in 15 fractions recording a median OS of 9 months. Westover et al. and Pollom applied the same schedule of treatment to all stages of disease, reporting a median OS of 12.5 months and 15.1 months, respectively [23, 24]. The differences reported in these studies may be related to patient selection and prescribed dose range. Better OS results were obtained in the SOCCAR study with an OS of 24.3 months for inoperable patients treated with radical intent and a schedule treatment of 55 Gy/20 fractions [25]. Another relevant radiotherapy scheme, 2.75 Gy/24 fractions associated to concurrent chemotherapy yielded an impressive median OS rate of 31.5 months [26].

Notwithstanding that stereotactic treatment on lung cancer has demonstrated the feasibility of AHR [12], one of the major concerns about its use is the potential toxicities [27]. A systematic review of the literature by Kaster et al. [28] on hypofractionation in locally advanced NSCLC reported improving outcomes in stage-III NSCLC with some schedules of AHR in systematic concurrent chemotherapy. The authors analyzed AHR with a dose ranging 45–85.5 Gy in 15–35 fractions, with a dose per fraction ranging 2.3–3.5 Gy, and concluded that AHR may improve local control, increasing the biological effective dose.

In our study, however, the dose delivered to the primary tumor ranged 6–8 Gy/fraction inhomogeneous dose (increasing within the tumor), and the dose delivered to the involved mediastinal nodes ranged 5–7.5 Gy/fraction in 5 daily fractions (increasing the inhomogeneous dose within the involved mediastinal nodes). The acceptable toxicity profile of the patients determined the feasibility of the proposed treatment schedule in combination with sequential chemotherapy. As reported in other studies [28], especially Cannon et al. [29], patient toxicity was correlated with the dose delivered to the OaR in the majority of cases. In their phase-I study using AHR for locally advanced NSCLC, Cannon et al. treated patients without concurrent chemotherapy, showing that hypofractionation of up to 63.25 Gy in 25 fractions (2.5 Gy/fraction) is well tolerated when strict normal tissue constraints are maintained. The most severe reported toxicity correlated to the total prescribed dose was G4–5 in the proximal bronchial tree and surrounding vasculature. Timmerman et al. [30] described a high potential damage of the central structures, such as complications due to the use of stereotactic body radiotherapy (SBRT) for the treatment of early stage NSCLC.

Hence, we also prescribed 30 Gy close to the central region positioning the inhomogeneous dose point of 40 Gy away from the bronchial structure so as to spare the bronchial tree (see Fig. 2) and avoid any G4–5 bronchial and vascular toxicity. We recorded no G4–5 toxicity for any of the OaR, probably as a result of the dose constraints because IMRT can considerably reduce the irradiated volume of the OaR while maintaining adequate dose coverage to the target, as also reported by Liu et al. [31] and also thanks to IGRT. Our data revealed G4 neutropenia and leucopenia related to chemotherapy, as 29% of chemotherapy was administered at a reduced dose, in particular for docetaxel. At the end of the protocol, 41% of patients had radiologically and histologically proven disease down-staging, whereas 59% had stable disease with 76% RR according to RECIST criteria 1.1. In particular, we recorded 18% of CR, 65% of involved lymph nodes down-staging, and 41% of primary tumor down-staging. The mediastinal downstaging is an important objective to reach for radiation oncologist and probably this fractionation could be considered as the first step to increase further the dose prescription to involved mediastinal nodes.

Indeed, one of the major issues in the treatment of locally advanced stage-IIIB NSCLC is locoregional control improvement. A relatively recent meta-analysis [32] of six randomized trials comparing concomitant vs. sequential chemoradiotherapy has shown that the former has a benefit in terms of locoregional progression (p = 0.01) and a lower rate of locoregional progression of disease at 5 years (28.9% vs. 35%), whereas no difference was found in terms of distant metastasis (p = 0.69). The Auperin study concluded that the concomitant approach yields better OS than sequential chemoradiotherapy due to better LC, which is achieved by radio-sensitizing the tumor with simultaneous application of chemotherapy. In our cohort, stage-IIIB NSCLC patients (88%) were able to undergo AHR with this treatment schedule, as adequate locoregional control sequential to chemotherapy had improved.

The literature reports that a high dosage per fraction, such as 3 Gy concurrent to chemotherapy with two agents, could lead to severe toxicity, in particular with the use of 3-dimensional conformal techniques [33]. We administered 6 Gy/fraction without reporting any G4–5 toxicity in normal tissue using intensity modulated arch therapy in tomotherapy in order to spare the OaR. Avoiding the contour of isotropic margin to the GTV, we irradiated a limited volume of normal pulmonary tissue. An important issue in our study was dosage appropriateness. We used BED10 at the isocenter as a function of tumor size (mean tumor volume was 150 cc) [34]. The calculated mean dose to the tumor was 74 Gy. With regard to the nodal volume, we used BED10 at the isocenter with a calculated mean dose of 54 Gy. Similarly to the literature data, our results confirmed the efficacy of the delivered doses.

The CHART study introduced continuous AHR in a randomized trial that showed better survival than conventional fractionation [35]. The final results of the CHARTWEL trial have laid down the basis for dose intensification trials for locally advanced NSCLC [36]. More recently, van Baardwijk published the results of a median OS of 25 months in a phase-II trial based on individualized accelerated radiotherapy concurrent with chemotherapy [37].

In the RTOG 0617 protocol a high number of deaths were reported in the arm receiving 74 Gy/fraction, probably due to radiotherapy-related normal tissue toxicity, even if the toxicity profile of these patients was the same as of those in the 60 Gy/fraction arm [11]. To avoid severe G4–5 toxicity, we used IMAT with tomotherapy, administering radiotherapy between chemotherapy cycles (between days 15 and 19 after the second chemotherapy cycle).

Recently, the PACIFIC study [38] reported the best PFS with radiochemotherapy treatment, concomitant or sequential followed by an anti PD-L-1 antibody, Durvalumab, in patients with inoperable locally advanced NSCLC. The median PFS was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with Durvalumab vs. 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65). The OS rate at 24 months was 66.3% (95% CI, 61.7 to 70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided p = 0.005). This is the future of the treatment of locally advanced NSCLC, considering also that many data suggest that the best association with immunotherapy could be hypofractionation [39].

Among the limitations of our study are the fact that it was designed before the use of immunotherapy in this pateint setting, the long period of accrual, restricted cohort of patients, i.e. Twenty-three enrolled patients, of whom only 17 were eligible, which was probably the greatest limitation in consideration of the results obtained for toxicity, PFS and OS. Furthermore, the accrual process was complicated as stage-IIIB lung cancer often hides stage-IV metastases and the trial was closed early, prior to first planned interim analysis, due to poor accrual. Another limitation of the study was the lengthy time between the last RT fractionation and the start of the last two chemotherapy cycles. The calculated period was an average of 28 days, even though a period of up to 15 days had been established, according to the protocol. One reason for this delay was that FBS was performed later than the established period due to organizational issues. Another drawback of the study was that brain CT was routinely performed in place of brain MRI.

Conclusions

In conclusion, chemo-radiotherapy is the gold standard in the treatment of unresectable stage-III locally advanced NSCLC. Since this kind of treatment is characterized by high toxicity, it is pivotal to counterbalance good results with acceptable toxicity. With similar rates of efficacy, a shorter treatment time would reduce overall treatment costs and improve patient compliance. As no high-grade radiotherapy-related toxicity was observed, the dose delivered to the tumor and lymph nodes might be increased. Finally, it is important to underline that the new technologies now allow for high radiation dose delivery, which can be associated with new targeted therapies.

Availability of data and materials

All data generated or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

3D-CRT:

3-dimensional conformal radiotherapy

AHR:

Accelerated hypofractionated radiotherapy

CTV:

Clinical target volume

DVHs:

Dose volume histograms

EBUS:

Endoscopic bronchial esophageal ultrasound

FEV:

Forced expiratory volume

G-CSF :

Granulocyte-colony stimulating factor

GTV:

Gross tumor volume

IGRT:

Image guided radiotherapy

IMAT:

Intensity modulated arc therapy

LN FNA:

Guided fine needle aspiration

MFS:

Metastasis-free survival

NSCLC:

Non-small-cell lung cancer

OaR:

Organs at risk

OS:

Overall survival

PFS:

Progression-free survival

RR:

Response rate

SCLC:

Small-cell lung cancer

References

  1. 1.

    Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med. 2011;32:1–61.

  2. 2.

    Boyle P. Cancer, cigarette smoking and premature death in Europe: a review including the Recommendations of European Cancer Experts Consensus Meeting, Helsinki, October 1996. Lung Cancer. 1997;17(1):60.

  3. 3.

    Ishida K, Hirose T, Yokouchi J, Oki Y, Kusumoto S, Sugiyama T, et al. Phase II study of concurrent chemoradiotherapy with carboplatin and vinorelbine for locallyadvanced non-small-cell lung cancer. Mol Clin Oncol. 2014;2:405–10.

  4. 4.

    Curran WJ, Scott CB, Langer CJ, Komaki R, Lee JS, Hauser S, et al. Long term benefit is observed in a phase III comparison of sequential vs concurrent chemoradiation for patients with unresected stage III NSCLC:RTOG 9410. Proc Am Soc Clin Oncol. 2003;22:2499.

  5. 5.

    Fournel P, Robinet G, Thomas P, Souquet PJ, Léna H, Vergnenégre A, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol. 2005;23:5910–7.

  6. 6.

    Non-Small Cell Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using update data on individual patients from 52 randomized clinical trial. BMJ. 1995;311:899–909.

  7. 7.

    Perez CA, Stanley K, Rubin P, Kramer S, Brady L, Perez-Tamayo R, et al. A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the radiation therapy oncology group. Cancer. 1980;45:2744–53.

  8. 8.

    Rosenzweig KE, Fox JL, Yorke E, Amols H, Jackson A, Rusch V, et al. Results of a phase I dose-escalation study using three-dimensional conformal radiotherapyin the treatment of inoperable nonsmall cell lung carcinoma. Cancer. 2005;103:2118–27.

  9. 9.

    Bradley J, Graham MV, Winter K, Purdy JA, Komaki R, Roa WH, et al. Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys. 2005;61:318–28.

  10. 10.

    Belderbos JS, Heemsbergen WD, De Jaeger K, Baas P, Lebesque JV. Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66:126–34.

  11. 11.

    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;2:187–99.

  12. 12.

    Arimoto T, Usubuchi H, Matsuzawa T, et al. Small volume multiple non-coplanar arc radiotherapy (SMART) for tumors of the lung, head & neck and the abdominopelvic region. In: Lemke HU, Vannier MW, Inamura K, et al., editors. Computer assisted radiology and surgery ‘98. Amsterdam: Elsevier science; 1998. p. 257–61.

  13. 13.

    Polico R, Stea L, Antonello M, Princivalli M, Marchetti C, Busetto M, et al. The polycentric multiple arc complanar technic, or telebrachytherapy. A 4-year experience (an innovative way for the local control of solid neoplasms). Radiol Med. 1995;90:113–23.

  14. 14.

    Hennequin C, Tredaniel J, Chevret S, Durdux C, Dray M, Manoux D, et al. Predictive factors for late toxicity after endobronchial brachitherapy: a multivariate analysis. Int J Radiat Oncol Biol Phys. 1998;1:21–7.

  15. 15.

    Trédaniel J, Hennequin C, Zalcman G, Walter S, Homasson JP, Maylin C, et al. Prolonged survival after high-dose rate endobronchial radiation for malignant airway obstruction. Chest. 1994;105:767–72.

  16. 16.

    Grills IS, Di Yan D, Martinez AA, Vicini FA, Wong JW, Kestin LL. Potential for reduced toxicity and dose escalation in the treatment of inoperabile non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation. Int J Radiat Oncol Biol Phys. 2003;57:875–90.

  17. 17.

    Cancer Therapy Evaluation Program. Common terminology criteria for adverse events, version 3.0, DCTD, NCI, NIH, DHHS, 2003. Publish date: August 9, 2006. http://ctep.cancer.gov.

  18. 18.

    Johnson DH, Stupp J, Greco FA, Stewart J, Merrill W, Malcolm A, et al. Neoadjuvant cisplatin plus vinblastine chemotherapy in locally advanced NSCLC. Cancer. 1991;68:1216–20.

  19. 19.

    Perez CA, Bauer M, Emami BN, Byhardt R, Brady LW, Doggett RL, et al. Thoracic irradiation with or without levamisole (NSC#177023) in unresectable NSCLC. A phase III randomized trial of the RTOG. Int J Radiat Oncol Biol Phys. 1988;15:1337–46.

  20. 20.

    Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluscak J, Curran WJ. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. JCO. 2005;23:5883–91.

  21. 21.

    Wurstbauer K, Deutschmann H, Dagn K, Kopp P, Zehentmayr F, Lamprecht B, et al. DART-bi (dose-differentiated accelerated radiation therapy, 1.8 twice daily)-a novel approach fon non-resected NSCLC: final resultsof a prospective study, correlating radiation dose to tumor volume. Radiat Oncol. 2013;8:49.

  22. 22.

    Swanick CW, Lin SH, Sutton J, Naik NS, Allen PK, et al. Use of simultaneousradiation boost achieves high control rates in patients with non-small-cell lung cancerwho are not candidates for surgery or conventional chemoradiation. Clin Lung Cancer. 2015;16:156–63.

  23. 23.

    Pollom EL, Qian Y, Durkee BY, von Eyben R, Maxim PG, Shultz DB, et al. Hypofractionated intensity modulated radiotherapy for patients with non small cell lung cancer. Clin Lung Cancer. 2016;17:588–94.

  24. 24.

    Westover K, Loo BW, Gerber DE, Iyengar P, Choy H, et al. Precision hypofractionated radiation therapy in poor performing patients with non small cell lung cancer: phase 1dose escalation trial. Int J Radiat Oncol Biol Phys. 2015;93:72–81.

  25. 25.

    Maguire J, Khan I, McMenemin R, O’Rourke N, McNee S, et al. SOCCAR: a randomized phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III non small cell lung cancer and good performance status. Eur J Cancer. 2014;50:2939–49.

  26. 26.

    Walraven I, van den Heuvel M, van Diessen J, Schaake E, Uyterlinde W, et al. Long term follow up of patients with locally advanced receiving concurrent hypofractionated chemoradiotherapy with or without cetuximab. Radiother Oncol. 2016;118:442–6.

  27. 27.

    Videtic GMM, Donington J, Giuliani M, Heinzerling J, Karas TZ, Kelsey CR, et al. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: executive summary of an ASTRO evidence-based guideline. Pract Radiat Oncol. 2017;7:295–301.

  28. 28.

    Kaster TS, Yaremko B, Palma DA, Rodrigues GB. Radical-intent hypofractionated radiotherapy for locally advanced non small cell lung cancer. Clin Lung Cancer. 2015;16:71–9.

  29. 29.

    Cannon DM, Mehta MP, Adkison JB, Khuntia D, Traynor AM, Tomé WA, et al. Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer. J Clin Oncol. 2013;31:4343–8.

  30. 30.

    Timmerman R, McGarry R, Yiannoutsos C, Papiez L, Tudor K, DeLuca J, et al. Excessive toxicity when treating central tumors in a phase ii study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 2006;24:4833–9.

  31. 31.

    Liu HH, Wang X, Dong L, Wu Q, Liao Z, Stevens CW, et al. Feasibility of sparing lung and other thoracic structures with intensity modulated radiotherapy for non small cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;58:1268–79.

  32. 32.

    Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181–90.

  33. 33.

    Machtay M, Washam C, Devine P. Pilot study of accelerated radiotherapy with concurrent chemotherapy for stage III non small cell lung cancer. Semin Oncol. 2005;32:S9–12.

  34. 34.

    Parisi E, Romeo A, Sarnelli A, Ghigi G, Bellia SR, Neri E, et al. High dose irradiation after pleurectomy/decortication or biopsy for pleural mesothelioma treatment. Cancer Radiother. 2017;21:766–73.

  35. 35.

    Saunders M, Dische S, Barrett A, Harvey A, Gibson D, Parmar M. Continuous hyperfractionated radiotherapy (CHART) versus conventional radiotherapy in non small cell lung cancer: a randomized multicentre trial. Lancet. 1997;350:161–5.

  36. 36.

    Baumann M, Herrmann T, Koch R, Matthiessen W, Appold S, Wahlers B, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non small cell lung cancer (NSCLC). Radiother Oncol. 2011;100:76–85.

  37. 37.

    Van Baardwijk A, Reymen B, Wanders S, Borger J, Ollers M, Dingemans AM, et al. Mature results of a phase II trial on individualized accelerated radiotherapy based on normal tissue constraints in concurrent chemo-radiation for stage III non small cell lung cancer. Eur J Cancer. 2012;48:2339–46.

  38. 38.

    Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with Durvalumab after Chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379:2342–50.

  39. 39.

    Kumar SS, Higgins KA, McGarry RC. Emerging therapies for stage III non-small cell lung cancer: stereotactic body radiation therapy and immunotherapy. Front Oncol. 2017;7:197.

Download references

Acknowledgments

The authors thank Veronica Zanoni and Cristiano Verna for editorial assistance.

Biostatistics and Clinical Trials Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via P. Maroncelli 40, 47014 Meldola, Italy.

Tel.: + 39 0543 739262, Fax: + 39 0543 739290, E-mail: emanuela.scarpi@irst.emr.it

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

EP conceived and designed the study, collected and assembled the study data, analyzed and interpreted the data, drafted the manuscript. GGe conceived and designed the study, analyzed and interpreted the data. AS analyzed and interpreted physical data. GGh collected and assembled the study data. DA collected and assembled the study data. MAB collected and assembled the study data. AR analyzed radiological data. GGa analyzed radiological data. AT analyzed and interpreted the data. ES and MM performed the statistical analysis. RP and AR revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Correspondence to Elisabetta Parisi.

Ethics declarations

Ethics approval and consent to participate

This study was approved by IRST IRCCS AVR Ethics Committee (approval no. 331 of 05/11/2008) and was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All patients gave written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

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.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Parisi, E., Genestreti, G., Sarnelli, A. et al. Accelerated hypofractionated radiotherapy plus chemotherapy for inoperable locally advanced non-small-cell lung cancer: final results of a prospective phase-II trial with a long-term follow-up. Radiat Oncol 14, 112 (2019) doi:10.1186/s13014-019-1317-x

Download citation

Keywords

  • Inoperable locally advanced non-small-cell lung cancer
  • Accelerated hypofractionation
  • Intensity modulated arc therapy (IMAT)
  • Radiotherapy and chemotherapy

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Please note that comments may be removed without notice if they are flagged by another user or do not comply with our community guidelines.