Cancer Investigation

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What is changing in radiotherapy for the treatment of locally advanced nonsmall cell lung cancer patients? A review Niccoló Giaj-Levra, Francesco Ricchetti & Filippo Alongi To cite this article: Niccoló Giaj-Levra, Francesco Ricchetti & Filippo Alongi (2016): What is changing in radiotherapy for the treatment of locally advanced nonsmall cell lung cancer patients? A review, Cancer Investigation, DOI: 10.3109/07357907.2015.1114121 To link to this article: http://dx.doi.org/10.3109/07357907.2015.1114121

Published online: 25 Jan 2016.

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Date: 28 January 2016, At: 11:03

CANCER INVESTIGATION http://dx.doi.org/./..

REVIEW

What is changing in radiotherapy for the treatment of locally advanced nonsmall cell lung cancer patients? A review Niccoló Giaj-Levra, Francesco Ricchetti, and Filippo Alongi

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Radiation Oncology Department, Sacro Cuore-Don Calabria Hospital, Negrar-Verona, Italy

ABSTRACT

ARTICLE HISTORY

Radiotherapy treatment continues to have a relevant impact in the treatment of nonsmall cell cancer (NSCLC). Use of concurrent chemotherapy and radiotherapy is considered the gold standard in the treatment of locally advanced NSCLC but clinical outcomes are not satisfactory. Introduction of new radiotherapy technology and chemotherapy regimens are under investigation in this setting with the goal to improve unsatisfactory results. We report how radiotherapy is changing in the treatment of locally advanced NSCLC.

Received  December  Revised  October  Accepted  October 

Introduction Radiotherapy alone or in association with chemotherapy has a major impact in the treatment of nonsmall cell lung cancer (NSCLC). The role of loco-regional treatment has been demonstrated in several clinical trials with a statistical impact on overall survival (OS) in NSCLC patients (1–3). In inoperable locally advanced (LA) Stage III NSCLC, combined platinum based chemotherapy and radical radiation dose of 64–66 Gy in 32–33 fractions is considered the standard approach with a loco-regional control probability of 40% (4). As reported in a meta-analysis, an absolute benefit on OS of 5.7% at 3 years and 4.5% at 5 years in the concurrent chemo-radiotherapy setting was demonstrated, compared with a sequential chemoradiotherapy approach (5). This result can be justified by an increase on the loco-regional control, with a decrease in relapse of 6% at 3 years in concurrent chemo-radiotherapy treatment. Nevertheless, no statistical difference in distant progression probability was found when the sequential and concurrent approaches were compared (HR 1.04; 95% CI, 0.86–1.25; p = .69) (5). Similar results were also reported in a recent retrospective analysis of seven clinical trials conducted by the Radiation Therapy Oncological Group (RTOG) CONTACT Niccoló Giaj-Levra Negrar, Italy. ©  Taylor & Francis Group, LLC

[email protected]

KEYWORDS

Radiotherapy; Non small cell lung cancer; Locally advanced; Altered fractionation; Dose escalation; New technology

which have demonstrated a significant correlation between local control (LC) and OS rates in concomitant chemo-radiotherapy (HR, 1.42; 95% CI, 1.26–1.60; p < .0001) (5). The concomitant approach has increased OS rates to 20–30%, with a median survival time of 18– 24 months (5). On the other hand, the use of a concomitant approach has increased treatment-related toxicity, including esophagitis and pneumonitis. In concurrent treatment, 18% of patients reported grade 3– 4 oesophageal acute toxicity compared with 4% in sequential treatment. In addition, the use of concurrent chemo-radiotherapy approach was associated with an increase of clinically relevant radiation pneumonitis rate with a range between 10% and 40% (6–8). For these reasons, less than 40% of patients are eligible to concurrent chemo-radiotherapy treatment and due to comorbidities, age and performance status (PS) most of them receive a sequential chemo-radiotherapy approach (9,10). The unsatisfactory clinical outcomes in terms of OS and progression free survival (PFS) after radiotherapy and chemotherapy in LA NSCLC could be related to: (a) an inadequate therapeutic dose to the primary cancer, (b) an excessive dose to normal tissues, (c) a large tumor/target volumes to be treated with a limitation on radiation dose prescription.

Radiation Oncology Department, Sacro Cuore-Don Calabria Hospital, Via Don A. Sempreboni , 

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Currently, several studies are investigating the use of higher dose of chemotherapy and a more accurate radiation planning and delivery by means of the use of functional images for target definition (PET-TC), 4D computed tomography (4D-CT), intensity modulated radiation therapy (IMRT) and adaptive radiotherapy. The goal of radiation treatment is to improve clinical outcomes (i.e. dose intensification/accelerated fractionation) and to reduce damage to the normal tissues. This article will discuss how radiation dose can be used in combination with chemotherapy to improve LC and OS.

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Material and methods PubMed (United States National Library of Medicine) and Scopus (Elsevier) databases were used to search studies published between January 1, 1980, and March 1, 2015, using the terms: locally advanced, primary, lung, cancer. Eligibility criteria for inclusion in the review were defined as manuscripts that (1) were written in English; (2) included number of patients treated with standard and altered fractionations; (3) presented new approaches to treatment of NSCLC; (4) were reports of phase II and III clinical trials.

Dose escalation

Tumor dose of 60 Gy in 30 fractions was established as the standard treatment in RTOG 7301. This randomized trial evaluated, in 365 patients, three different dose prescriptions: 40 Gy in 20 fractions (arm 1), 50 Gy in 25 fracionts (arm 2) and 60 Gy in 30 fractions (arm 3). Tumor dose prescription of 60 Gy was established as the standard treatment according to the finding of intra-thoracic failure rates of 52% in arm 1, 42% in arm 2 and 33% in arm 3 (11). For approximately 20 years, no other trials were designed to compare higher dose with lower dose prescription. In the 90s retrospective analysis and pooled studies reconsidered the use of dose escalation to improve clinical outcomes. A significant study on the role of dose escalation was reported by Kong et al. in 106 patients with a diagnosis of NSCLC—Stage I and IIIA/B treated with a progressive dose escalation of 63–69 Gy, 74–84, 92–103 Gy. No data about acute and late toxicity were reported. LC probability at 5 years was, respectively, of 12%, 35%,

and 49%, OS at 5 years was 4%, 22%, and 28%, respectively. The conclusion of the paper was that for each 1 Gy radiation dose increment an improvement in 5year LC by 1.25% and a decrease of death risk by3% was observed (12). Phase I/II RTOG 9311 trial reported the outcome of a dose-escalated 3D conformal radiotherapy in 177 medically inoperable or unresectable stage I-III NSCLCs stratified at escalation dose level according to parameters V20 Gy (percentage of the total lung volume that received > 20 Gy (13). Patients with a V20 < 25% received escalation to 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions and 90.3 Gy in 42 fractions. Patients with a V20 between 25 and 36% received a dose escalation of 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions and 83.8 Gy in 39 fractions. Seven patients with a V20 Gy < 25% had developed an acute 3 or worse toxicity: 4 cases associated with chemotherapy and three patients with a dose prescription of 90.3 Gy (they developed acute pneumonitis). On the other group 2 patients with V20 between 25 and 36% treated with a dose prescription of 77.4 Gy developed acute pneumonitis. Analyzing late toxicity, grade 3 or worse was reported in: 6 patients with a dose prescription of 70.9 Gy who had lung toxicity, 8 patients treated to 77.4 Gy and in 5 patients treated to 90.3 Gy. Starting from these results a radiation dose escalation was considered safe using 3D conformal techniques to 83.8 Gy in patients with a V20 < 25% and 77.4 Gy in patients with V20 between 25 and 36%. In the combined chemo-radiotherapy setting several studies evaluated the appropriate prescription. RTOG trial 0117 was a study investigating dose-escalation radiation therapy with concomitant carboplatin and paclitaxel chemotherapy. In this phase II study a dose prescription of 74 Gy was administered to 53 patients. In stage III disease this study demonstrated a median OS of 21.6 months, PFS of 10.8 months and 12 months OS and PFS of 72.7% and 50% respectively. Twelve patients presented grade 3 lung toxicity and two cases of grade 5 lung toxicity were reported (14). Other studies as North Central Cancer Treatment group (NCCTG) N0028 and Cancer and Leukemia Group B (CALGB) 30105 trials confirmed efficacy in the use of 74 Gy in terms of clinical outcomes and toxicity profile (15,16). Socinski et al. started to analyze in 62 patients the impact of dose escalation with a dose prescription of 74 Gy compared with 60 Gy in a phase I/II clinical trial. Analyzing all the population, median survival was

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26 months, with an OS at 12 months of 71% and at 3 years of 40%. PFS at 1 year and 3 years were respectively 47% and 29%. No dose-limiting toxicity was observed in dose escalation from 60 Gy to 74 Gy and esophagitis was the major toxicity during radiotherapy, even though only 8% of patients developed a grade 3/4 esophagitis (15). Clinical trial CALGB 30105 evaluated the use of induction chemotherapy followed by concurrent chemo-radiotherapy in stage III NSCLC. Sixty-nine patients were randomized to two different chemotherapy treatments—carboplatin plus gemcitabine or paclitaxel—with a dose escalation thoracic radiotherapy (74 Gy/2 Gy per fraction). The use of gemcitabine was associated with a higher toxicity profile in terms of grade 3 esophagitis (39% vs. 16%) and grade 3 fatigue (35% vs. 11%). An unacceptable grade 4–5 lung toxicity was reported in gemcitabine arm and it was closed prematurely. The carboplatin and paclitaxel chemotherapy obtained a median survival time of 24 months compared to 12.5 months in carboplatin and gemcitabine (p-value: n.a). CALGB 30105 showed induction chemotherapy followed by carboplatin/paclitaxel plus 74 Gy had 3-years OS of 37% (16). CALGB 30105 demonstrated that induction chemotherapy with carboplatin plus gemcitabine and concurrent gemcitabine and conformal radiotherapy was not feasible because of treatment related toxicity. However, concurrent carboplatin and paclitaxel with 74 Gy and conformal radiotherapy yielded a median survival of 24 months with a 12% rate of grade 3 or higher pulmonary toxicity. Starting from these findings, RTOG 0617 trial was activated in order to establish the role of radiation dose escalation (74 Gy) with combined carboplatin and paclitaxel (16). RTOG 0617 compared 60 Gy (in 6weeks) versus 74 Gy (in 7.5 weeks), in a 2×2 design where patients were also randomized to receive or not cetuximab (17). Bradley et al. reported an OS of 28.7 months for patients who received standard dose radiotherapy compared with 20.3 months for those who received highdose radiotherapy. Median survival in patients who received cetuximab was 21.3 months compared to 24.0 months in those who did not (p = .29). Local failure in patients who completed standard radiation treatment was 30.7% at 2 years compared with 38.6% in high dose arm. Cetuximab arm had a higher probability to be associated with a local failure with no cetuximab arm (38.2% vs. 30.7%; p = .20). No

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statistical difference was also described in PFS and distant metastasis probability (DMP) in both arms with a p-value of 0.12 and 0.48, respectively. The use of cetuximab did not improved PFS and did not increase DMP (p = .89 and p = .099). Analyzing toxicity profile there were no difference in severe pulmonary events in both groups (44 patients in standard-dose group vs. 39 in high-dose group p = .71). Severe esophagitis was more frequent in high-dose chemo-radiotherapy group (43 of 207 vs. 16 of 217; p < .0001). On univariate analysis several variables were associated with an increased risk of death: gross tumor volume, planning target volume, lung V5, heart V5, and heart V30. On multivariate analyses radiation dose prescription of 60 Gy, maximum esophagitis grade, planning target volume, heart V5 and V30 were found to be predictors of OS. Regarding statistical analysis several consideration can be made. As previously reported by Wiersma et al., planning target volume was correlated with OS in patients with stage III NSCLC. Patients with PTV > 700 cc (with or without N3 nodal disease) had a significantly shorter OS than patients with PTV ࣘ 700 cc with N3 nodal stage (18). In patients with a larger target volume the benefits of concurrent chemo-radiotherapy are modest and sequential treatment could be a less toxic approach for investigating dose escalation. The use of dose escalation prescription with radiation dose of 74 Gy and 86 Gy delivered after chemotherapy was associated with a higher incidence of brochial stenosis (4% and 25%, respectively) and this complication can increase when chemo and radiotherapy are used concurrently (19). Analyzing lung dose distribution no difference in V5 was reported in 74 Gy (58%) versus 60 Gy (57.7%) dose prescription. Lung V20 was higher in the 74 Gy group (28.7% versus 30.9%; p = .0012) and mean lung dose was significantly higher in the 74 Gy group (mean dose 16.5 Gy versus 18.9 Gy; p < .0001). Unexpectedly the use of IMRT was not associated with a reduction in toxicity probability. In fact the use of IMRT allows clinicians to obtain, compared to conformal radiotherapy, better radiotherapy planning parameters as V20 and mean lung dose and reduce the probability to develop lung toxicity (i.e. radiation pneumonitis) (20). As reported in the literature, V20 values of 35–37% and MLD value of 20–23 Gy have been considered safe but 10–15% of patients can still develop a sever radiation pneumonitis when lower doses are delivery (21).

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RTOG 0617 confirmed the impact of cardiac dose (V5) on survival. This data was previously described by Hardy et al. where a higher risk of ischemic heart disease and cardiac dysfunction was registered in patients treated with a chemo-radiotherapy treatment for left sided lung cancer (22) and myocardial hypoperfusion was reported with cardiac dose of 45 Gy or higher (23) but more studies are necessary to confirm these results. Another relevant aspect in the combined chemoradiotherapy approach is represented by the choice of the drugs to use. As reported in the literature, chemotherapy may increase lung toxicity and some chemotherapeutic agents, as gemcitabine, are not suitable (such as gemcitabine) for routine use with concurrent radiotherapy (24). A recent meta-analysis confirmed also that the risk of radiation pneumonitis is higher after concurrent chemo-radiotherapy in patients aged > 65 years, receiving carboplatimpaclitaxel (25). The use of daily dose fractionations exceeding 2 Gy, the V20 parameter and lower-lobe tumor locations were reported as predictors of fatal pneumonitis (26–28). Finally, the last consideration for radiotherapy treatment concerns Image-guided techniques (IGRT) and organ motion. IGRT reduces repositioning errors and it has been used to monitor the treatment region and/or to adapt dose distribution to the possibly changing target and organs at risk during radiation (29). Nowadays, four-dimensional CT (4DCT), a tool to follow respiratory motion, is a common strategy to reduce margins of the target and subsequently healthy tissue involvement. In RTOG 0617, where the dose was increased to 74 Gy, the adoption of the previous procedures should be considered “mandatory”, and not “encouraged” as reported in the trial. Indeed, this could be a potential pitfall in the results interpretation of the study. RTOG 0617 reported a violation of the protocol parameters in 6% of patients in 60 Gy group and 9% of patients in 74 Gy group. This data should be considered

analyzing clinical trial results. In fact, quality assurance data from radiotherapy trials reveals that mistakes in protocol requirements are associated to decrease survival, poorer LC and more toxicity (30). Weber et al. reported rates of RT major deviations in prospective trials, ranging from 11.0% to 48.0% (31). An impact on OS by radiotherapy deviation was demonstrated in the HD7 trial (32). A poor quality on radiation treatment may have a detrimental effect on LC as demonstrated in the TROG 02.02 were LC was improved in patients who received an appropriate delivery (33). Several potential reasons can explain radiation protocols violations: (1) misinterpretation of the protocol or ambiguities in the protocol, (2) deliberate deviation from a protocol because it is perceived to be too radically different from standard practice, (3) deliberate change of methods to prevent or treat toxicity with a potential impact on future clinical indications (34). Principle studies summarized in Table 1. In summary, although the RTOG 0617 trial could be of significant value for its potential declination in clinical practice, further studies, including PETCT and IGRT procedures, must be evaluated in the setting of high doses, considering that several phase I/II trials with 74 Gy and concurrent platinum-based chemotherapy demonstrated safe profile and promising results (15,16). Altered fractionation Hyperfractionation and accelerated fractionation A crucial issue regards the overall treatment time: it has been recognized that prolongation of treatment time seems to be detrimental to LC and OS. The loss of survival rate is reported to be of 1.6% per day of prolongation beyond 6 weeks (35). Indeed, this could justify that the prolonged arm (74 Gy) of RTOG 0617 showed a worse outcome. Further studies reducing treatment time, maintaining high biological effective

Table . Phase II and III dose escalation trials. Study CALGB  Phase II [ ] Arm A Paclitaxel/carboplatin/RT Arm B Gemcitabine/carboplatin/RT RTOG  Phase III [ ] Arm A Carbo+Paclitaxel/standard dose Arm B Carbo+Paclitaxel/high dose Arm C Carbo+Paclitaxel+Cetuximab/standard dose Arm D Carbo+Paclitaxel+Cetuximab/high dose

N        

LC: local control; PFS: progression free survival; OS: overall survival.

RT dose

LC

PFS

OS

 Gy  Gy

— —  yr .% .% .% .%

 months .% .%  yr .% .% .% .%

 months .% .%  yr .% .% .% .%

 Gy  Gy  Gy  Gy

Median Survival (months) . . . .  

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dose (moderate hypofractionation, simultaneous integrated boost) could be useful in this setting. In fact, it has been known that prolongation of overall treatment is detrimental to local control and overall survival in NSCLC and the loss of survival rate is reported to be of 1.6% per day of prolongation beyond 6 weeks (36,37). In order to improve the clinical outcomes and the therapeutic dose to the primary lung cancer, without increase in treatment time, two types of altered fractionations have been studied: hyperfractionation (two or three fractions per day with a lower dose per fraction compared to the standard treatment duration), accelerated fractionation (using a standard fraction size and total radiation dose, given over a shorter overall time), or a combination of hyperfractionation and acceleration. The aim of hyperfractionated treatment is to take advantage of the difference in the dose-response relationship between tissue that are early responding, such as skin and mucosa, and those that are lateresponding, such as lung and spinal cord. This difference is observed on the basis of a linear quadratic model. In this model, the dose-response relationship is made up of two components, a linear (α) component and a quadratic (β) component. The dose at which the α and β components of cell killing are equal is the α/β ratio. The α/β ratio for late-responding tissues is smaller than that for early-responding tissues, translating into more severe late reactions with fewer and larger dose fractions. Hyperfractionation allows for an increase in thoracic RT dose, usually of 20% to 30%, and at the same time preferentially spares late-reacting tissues with smaller fraction sizes. The objective of this regimen is to reduce repopulation in lung tumors with short potential doubling times by improving the timing of dose delivery. This alternative strategy adds little in terms of late effects because the dose per fraction is only slightly reduced, with approximately the same number of treatment fractions. RTOG 8311trial evaluated, in 350 patients, five different exclusive radiotherapy dose prescription (1.2 Gy BID to 60, 64.8, 69.6, 74.4 Gy, and 79.2 Gy). A survival benefit was shown in 69.6 Gy arm, in twice daily fractions of 1.2Gy, compared with lower dose; no significant improvement was found with higher dose. The median survival was 13 months and an overall survival at 2 years of 29% was reported (38). Overall toxicity was considered acceptable in all the arms of this

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trial, with only six grade 4 or worse acute radiotherapy related or chemoradiotherapy related toxic effects. No deaths were attributable to standard RT. Three deaths occurred that were caused by neutropenic sepsis prior to radiation in the CT/RT group, and two additional deaths with pneumonitis during or after radiation were reported. The subsequent trial RTOG 8808 and Eastern Cooperative Oncology Group (ECOG) compared three different setting: a standard fractionation of 60 Gy/30 fractions (arm 1), 60 Gy/30 fractions associated with induction chemotherapy (arm 2) and hyperfractionated regimes of 69.6 Gy in twice daily 1.2 Gy fractions (arm 3). The median survival for patients receiving standard treatment (arm 1) was 11.4 months compared with 13.2 months in patients treated with induction chemotherapy (arm 2) and 12 months in hyperfractionated regime (arm 3). The survival rate at 2 and 3 years were 21%–11% (arm 1), 32%–17% (arm 2) and 24–14% (arm 3), respectively. The log-ranked statistical comparison indicated that chemotherapy plus irradiation resulted in a superior survival (p = .04). The difference in early and late high-grade toxicity was not statistically significant in the two groups (39). The RTOG 9106 trial evaluated the 69.6 Gy arm in combination with cisplatin and etoposide compared with the same radiotherapy alone hyperfractionated arm used in RTOG 8311. The addition of chemotherapy increased the clinical outcome results with a median survival time of 18.9 months compared with 10.6 months in the radiotherapy alone. The 2 years overall survival was 36% and 22% (p = .014) (40). The phase II RTOG 9204 randomized clinical trial investigated the role of chemotherapy and hyperfractionated radiotherapy in locally advanced NSCLC. Arm 1 used an induction chemotherapy scheme with cisplatin and vinblastine followed by radiotherapy treatment (63 Gy in 34 fractions) associated with concurrent cisplatin alone. Arm 2 was concurrent cisplatin plus etoposide and hyperfractionated radiotherapy twice daily (69.6 Gy/58 fractions). Arm 2 demonstrated a significant time reduction to in-field progression. The time to in-field progression was significantly different by treatment regimen (p = .042). At 1 year the in-field progression was 32% in arm 1 compared with 20% in arm 2 (p = .009). No other statistically significant differences were identified between the two approaches (41). RTOG 9410 randomized clinical trial explored the use of sequential chemotherapy with cisplatin plus

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vinorelbine and a radiation prescription of 60 Gy/2 Gy (Arm A), concomitant chemo-radiotherapy with cisplatin plus vinorelbine and 60 Gy/2 Gy (Arm B) or cisplatin plus etoposide with hyperfractionated radiation treatment 69.6 Gy/1.2 Gy twice a day (Arm C). Arm B demonstrated a higher survival rate compared with hyperfractionated schedule (p = .046). The results from this trial demonstrated the role of conventional fractionation and concurrent chemotherapy, which is considered the gold standard treatment in good performance patients (42). A more intense approach was evaluated by UK clinicians with the use of hyperfractionated accelerated radiotherapy (CHART—Continuous Hyperfractionated Accelerated Radiation Therapy) schedule with a total dose prescription of 54 Gy, three fraction of 1.5 Gy per 7 days per week. The clinical trial, which enrolled 563 lung cancer patients, compared a conventional fractionation of 60 Gy/ 30 fractions and CHART. The 2-, 3-, and 5- year survival rates were 30, 18, and 12% in CHART protocol compared to 21, 13, and 7% in standard arm. CHART regimen resulted in longer survival and LC compared with conventional fractionation. In particular there was a 22% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 9% from 20 to 29% (p = .008) and a 21% reduction in the relative risk of local progression (p = .033) (43). On the basis of this result, the Phase III CHARTWEL trial was evaluated using a fractionation of 60 Gy in 2.5 weeks, (with 7 fractions per week) compared with a conventional schedule of 66 Gy in 6.5 weeks; the study enrolled 406 patients. No difference in clinical outcomes was reported in the two arms. The most important result of the CHARTWEL was the demonstration of a time factor for fractionated

radiotherapy in NSCLC, as LC after CHARTWEL was higher than after conventional fractionation, even if total dose was 10% lower in the hyperfractionated arm compared with conventional schedule (44). Two Phases II clinical trials started to evaluate the role of a combination of chemotherapy (INCH-trial with three cycle of induction chemotherapy and ECOG 2597 with two cycle of induction) and accelerated radiotherapy fractionation (CHARTWEL), but both trials were closed prematurely without any statistical difference on all clinical outcomes (45,46). A meta-analysis of hyperfractionated or accelerated radiotherapy for NSCLC (with or without chemotherapy) showed an absolute survival benefit of 2.5% at 5 years compared with conventional treatment (47). Analyzing data published in the literature comparing altered and conventional fractionation, no difference on PFS, loco-regional control, distant metastases were reported. Data coming from specific studies investigating accelerated and hyperfractionated fractionation are controversial. Positive results coming from CHART were not confirmed by CHARTWEL. Moreover, the use of altered fractionation increased acute toxicity, namely esophagitis. More studies are required to establish which radiotherapy regimen is the most suitable with concurrent chemotherapy. Principle studies are summarized in Table 2. In summary, modified radiotherapy schedules remain less commonly utilized than conventional fractionation, due in part to the logistical challenges as well as the increased toxicity profile.

Hypofractionation Hypofractionation represents the delivery of fewer fractions at an increased dose per fraction, typically

Table . Phase II hyperfractionated and accelerated trials. Study RTOG  Phase II [ ]

N

RT dose

CT prescription

Results



. Gy/. Gy (BID)  Gy/ Gy . Gy/. Gy (BID) . Gy/. Gy (BID) . Gy/. Gy (BID)  Gy/. Gy . Gy/. Gy (BID)  Gy/ Gy  Gy/. Gy (TID)

None None None Concurrent None Concurrent Induction Concurrent None None

Improvement in medial survival in >. Gy

 Gy/ Gy  Gy/. Gy (TID)

Induction/none Induction/none

RTOG  Phase II [ ] RTOG  Phase II [ ]

 

RTOG  Phase II [ ]



CHART [ ]



CHARTWEL [ ]



Survival rate @ – yrs comparable Median survival . mo RT+CT vs. mo in RT @ yrs failure: %vs.% @ yrs failure: %vs.% OS @  yrs % % No statistical differences

RT: radiotherapy; CT: chemotherapy; OS: overall survival; PFS: progression free survival; MTD: maximal tolerance dose; fx: fractions; mo: months.

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only once per day. Until recently, hypofractionation was not considered applicable because of the risk of severe adverse effects on the lung and other organs at risk (48). In the hypofractionated regimes a very limited number of clinical trials are available, most of them are small prospective Phase I/II trials or retrospective studies. A recent phase II clinical trial by Zhu et al. on stage III NSCLC explored a combination of hypofractionated radiotherapy schedules with an initial dose of 50 Gy in 20 fractions, followed by a sequential boost with dose per fraction of 3 Gy up to 65 or 68 Gy associated with an induction chemotherapy and one or two cycles of consolidation chemotherapy. The median survival was 19 months, overall survival and progression free survival at 3 years of 32.1% and 29.8% respectively. The 1-, 2-, 3-year loco-regional progression free survival rates were 69.6%, 60.9%, and 60.9% (49). In the UK the use of hypofractioned radiation treatment is considered the standard approach in LA NSCLC. A dose prescription of 55 Gy in 20 fractions was reported as feasible with a good toxicity profile, in a series of 600 patients compared with a standard fractionation. Patients with stage IA to IV were enrolled in the study. In the study 168 patients received a sequential chemo-radiotherapy treatment. OS of the chemotherapy group was not statistically significantly different compared to those who did not receive chemotherapy (21 months vs. 26 months; p = .332). For patients with stage III disease, there was a trend to improve survival in the chemotherapy group (21 months versus 19 months, p = .068). The 1, 2, 3, and 5 year OS rates were respectively 81%, 50%, 36% and 20%. Patients with a diagnosis of locally advanced NSCLC had a median survival of 20 months and 2 year survival of 40%. An excellent tolerability of the radiation treatment was recorded. No case of grade 3–5 was recorded (50). SOCCAR is a phase II randomized clinical trial to evaluate the impact of hypofractionated radiation treatment, with a dose prescription of 55 Gy in 20 fractions, associated with a concomitant or sequential chemotherapy approach with cisplatin and vinorelbine. The median survival was 24.3 months in concurrent setting compared to 18.4 months in sequential approach. An acceptable toxicity profile was reported. Three patients (2 in concurrent arm and 1 in sequential arm) presented grade 5 toxicity. Grade

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3 and above esophagitis and pneumonitis (concurrent versus sequential) were 8.8% versus 8.5% and 3.1% versus 5.2%, respectively. Overall survival at 2 years were 50% in concurrent approach and 46% in sequential. The 2-year progression free survival and locoregional progression were 34% and 47% in concurrent arm compared with 24% and 45% in sequential arm. Survival rates in both arms were comparable to RTOG 0617 results and to 74 Gy dose escalation approach (51). Kim et al. evaluated in a phase I/II clinical trial the impact of dose escalated hypofractionated Intensitymodulated Radiation Therapy associated with a concurrent chemotherapy treatment in 20 patients. Dose prescription was 48 Gy in 20 fractions and three different boost dose levels were used: 6.8 Gy/7, 20.0 Gy/7 and 22.7 Gy/7. One-year local progression-free survival and overall survival estimates were 81% and 58%, respectively, and the maximal tolerated dose of radiotherapy boost was 22.7 Gy/7 fractions (52). There are ongoing prospective trials evaluating the efficacy and safety of hypofractionated radiotherapy including a randomized phase III trial (NCT01459497) (51–53). Principle studies are summarized in Table 3. In summary, hypofractionation seems to be promising in selected patients but its role in LA NSCLC still remain not established mainly due to the absence of Phase III trials.

Table . Hypofractionated clinical trials. Study

N

RT dose

CT prescription

Zhu et al. Phase II [ ]



ࣙ  Gy/ Gy

Induction

SOCCAR Phase II [ ]



 Gy/. Gy

Concurrent   Gy/ . Gy plus . Gy/fx . Gy/fx . Gy/ fx

Median OS  mo Median PFS  mo @  years OS

Sequential

Kim et al. Phase I–II [ ]

Results

Seq: % Conc: % Good toxicity profile @  year

PFS: % Concurrent OS: % MTD:  Gy/ fx

RT: radiotherapy; CT: chemotherapy; OS: overall survival; PFS: progression free survival; MTD: maximal tolerance dose; fx: fractions; mo: months.

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New technical approach

A new therapeutic approach in order to improve the local control in patients with LA NSCLC is represented by stereotactic ablative radiation treatment (SABR) as a boost to the primary parenchymal lesion. Feddock et al. recently reported the feasibility of a SABR treatment to the parenchymal lesion in patients with a diagnosis of LA NSCLC (54). SABR treatment was added after the conventional chemo-radiation (60 Gy/ 30 fractions) treatment: prescription dose varied from 10 Gy in 2 fractions in peripheral lesion to 6.5 Gy in 3 fractions in the central tumors. After a median follow-up of 13 months patients with a radiation pneumonitis grade 4 or 5 were not reported and local control was 82.9%. Other experience of SABR after chemo-radiation treatment has been recently published (55). Sixteen patients received an IMRT treatment with a median dose of 50.4 Gy and a boost of 25 Gy in 5 fractions (median cumulative dose of 97Gy). After a median follow-up of 14 months, the overall survival was 78%, local control 76% and progression free survival of 42%. It was not reported any toxicity case of grade 3 or higher. Other clinical trials are ongoing to establish the role of SABR in patients with a diagnosis of locally advanced lung cancer, are ongoing, as reported in Table 4. In this setting, a relevant impact in radiotherapy treatment planning can be represented by the use of PET-CT imaging that supports target delineation. In fact, the integration of PET-CT systems in radiation therapy planning further provide improvements compared to CT alone in delineation of Tumor Volumes due to: (a) a better discrimination between atelectasis/lung cancer (56), (b) better identification of metastatic lymph nodes (57,58). (c) minimization of the interobserver contouring variability (59) that it could be relevant in ablative radiation treatment. Moreover, RTOG 0617 was the first experience in locally advanced NSCLC where the impact of PETCT strongly emerged as a crucial tool to exclude N3 (with supraclavear and/or contralateral hilar adenopathy) patients that probably would not take advantage in loco-regional treatment. An American study will explore the addiction of SABR (2 fraction of 10 Gy in peripheral lesion and 3 fraction of 6.5 Gy in central lesion) after chemotherapy and radiotherapy (59.4 Gy in 1.8 Gy per fraction) (60).

In a phase I ongoing trial, the Memorial SloanKettering Cancer Center is evaluating the role of SABR (prescription dose from 8 to 12 Gy × 5 fractions) with or without concurrent chemotherapy treatment with cisplatin or carboplatin in LA NSCLC patients without lymph nodal involvement (61). A tolerance explorative study by The Jonsson Comprehensive Cancer Center will analyze the role of image guided hypofractionated radiotherapy given together with hypofractionated radiotherapy boost and combined chemotherapy in patients not eligible to surgical resection. The primary endpoint is to determine the maximum tolerated dose and the secondary endpoint are local control, disease specific survival and overall survival (62). In summary, the use of stereotactic approach as a boost after conventional fractionation radiotherapy is to be considered an interesting approach. Nevertheless, more studies with larger data are necessary to establish the impact on clinical outcomes. Proton therapy

A new potential therapeutic approach in the treatment of NSCLC is proton therapy. The dosimetric advantage of protons over photons is now well established. The primary advantage in the use of proton therapy is the ability to deliver the required dose of radiation to the tumor site while reducing radiation exposure to adjacent normal tissues. Protons have a larger mass than photons and this results in a narrower beam and can allow a higher conformity to the tumor. Second, protons have a low penetration range, surrounding normal tissues are minimally irradiated and the integral dose received by a given patient is lower (63). A Bragg Peak is defined as the point at which photons/protons (and other heavily charged particles) deposit most of their energy. Proton has the potential role to reduce the dose to the normal tissue in particular to the lung and to the heart. Initial studies have demonstrated that in patients receiving a concomitant treatment of chemo-radiotherapy the overall survival is influenced by the mean dose to heart and lung (25,64). As previously described, univariate and multivariate analysis of RTOG 0617 demonstrated that lung V5, heart V5 and heart V30 were considered predictors of OS. A phase II clinical trial is evaluating the impact of concurrent chemotherapy with cisplatin (on Day 1) and vinorelbine (on Day 1 and Day 8) and proton

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Table . Phase I clinical trials ongoing. Number of trial

Phase

RT dose

SABR dose

Primary end point

Secondary end point

NCT

I

. Gy/#

Toxicity

Response

NCT NCT NCT NCT

I I I I

— HypoRT  Gy/# RT/CT

Peripheral:  Gy/ # Central: . Gy/ # --/# +/− chemo SABR boost SABR boost/# SABR/CT

Toxicity Toxicity Toxicity Toxicity

Response & progression LC/OS/DSS LC/OS/DSS —

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Fx: fractions; Hypo: hypofractionated radiotherapy; SABR: stereotactic ablative radiotherapy; LC: local control; OS: overall survival; DFS: disease free survival.

therapy in LA NSCLC. The preliminary results reported a median survival of 26.7 months with a good toxicity profile (65). In a Phase II Chang et al. evaluated in 44 patients with a diagnosis of stage III NSCLC the role of proton therapy. A dose prescription of 74 GyE in 37 fractions with weekly carboplatin and paclitaxel was used. Overall survival was 29.4 months without any grade 4– 5 acute and late toxicity. Nineteen patients developed distant metastases, 9 (20.5%) and 4 (9.1%) had local disease recurrence and regional lymph node progression, respectively (66,67). A new phase III clinical trial (RTOG 1308) will establish the role of high dose of radiation (74 Gy RBE) with the use of protons or photons. Principle studies are resume in Table 5. In summary, early results of proton therapy showed promising OS and good toxicity rated but longer follow-up is necessary for definitive conclusions on its potential role in the setting of LA NSCLC.

Isotoxic radiotherapy

An innovative therapeutic approach is represented by the isotoxic radiotherapy where the dose prescription is defined by the maximal dose achievable to the organ at risk. To minimize the risk of repopulation this approach was associated with an accelerated hyperfractionated treatment (INDAR) and concurrent chemotherapy (68). The rationale was to administer an accelerated high-dose treatment on the basis of individual normal tissue dose constraints. Table . Proton clinical trials. Study

N

RT dose

CT prescription

Results

Oshiro et al. Phase II [] Chang et al. Phase II []



 GyE/fr

Concurrent



 GyE/fr

Concurrent

Median OS . mo LR in  patients Median OS . mo No grade – toxicity

OS: overall survival; LR: local recurrence; mo: months.

In the period from 2006 onwards the mean radiation doe was 64.8 Gy given in 36 bi-daily fractions of 1.8 Gy which at least 8 hours of inter-fraction interval in an overall treatment time of 3.6 weeks was given. This is a biological equivalent of adose of 82 Gy in 41 daily fractions given in 8.2 weeks. From 2006, concurrent chemo-radiation was used. In the first three weeks, 30 twice-daily fractions of 1.5 Gy were given, followed by once-daily fractions of 2 Gy until a mean lung dose of 19 Gy was reached, with a minimum dose of 54 Gy and a maximum of 69 Gy. A mean radiation dose to the tumor and the involved lymph nodes of 65 Gy delivered in 5.5 weeks was given. This corresponds to a biological equivalent of 72 Gy given in 36 daily fractions in 7.2 weeks. Considering that most patients are not eligible to concurrent chemoradiotherapy because of comorbidities, age and performance status, the isotoxic approach represents a good alternative to increase the local control of the disease. A feasibility study by the Maastro group analyzed the tolerance in 28 patients with a diagnosis of NSCLC in stage II and III. A mild toxicity profile was recorded with the prescription of a hyperfractionated accelerated 3D-CRT approach (69). In a prospective study 166 patients were enrolled in a single arm study with the use of radiotherapy alone or after chemotherapy. The median prescription dose was 64.8 Gy and at a median follow up of 31.6 months the OS was 21 months with an acceptable toxicity profile (21). Van Baardwijk A et al. are evaluating the role of concurrent chemo-radiotherapy in patients with a diagnosis of locally advanced lung cancer in a phase II study. The preliminary results are encouraging with a good toxicity profile and an overall survival of 25 months. The median follow-up time was 30.9 months. Oneyear OS was 72.2% and 2-year OS 52.4%. Median OS in the different stages were as following: stage IIIA 24.2 months and stage IIIB 29.1 months (p = .51). The median PFS was 14.0 months with a 1-year PFS of 54.7% and a 2-year PFS of 35.5%. Eight patients

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(58.4%) showed recurrent disease: 5.1% (n = 7) an isolated local recurrence, 4.4% (n = 6) an isolated regional recurrence, 5.1% (n = 7) a combined local and regional recurrence and 27.0% (n = 37) distant metastases only (70). A recent update of the INDAR study, in the subgroup of patients with a diagnosis of NSCLC T4N0N1 or a single station Stage IIIA, reported the impact of isotoxic radiotherapy associated with a concurrent chemotherapy. At a median follow-up of 48 months and a median dose prescription of 65 Gy, the median the median OS for T4N0-1 patients was 34 months with 55% 2-year survival and 25% 5-year survival. In patients with a stage IIIA-N2 at a median follow-up of 50 months the median OS was 26 months with 2- and 5-year survival rates of 53% and 24% (71). In the individualized radiation protocols, RTOG 1106 trial is introducing the role of PET-CT comparing two arms. The first arm receives a concurrent treatment with chemotherapy (carboplatin and paclitaxel) and radiotherapy (60 Gy in 30 fractions) and the second arm a concomitant chemotherapy treatment and image guided radiotherapy daily for 5 days a week for 3–4 weeks (46.2 Gy in 21 fractions) and then, based on PET-CT scan results, individualized adaptive radiotherapy for 2–3 week (19.8–34.2 Gy in 9 fractions) (72). In summary, isotoxic radiotherapy seems to be a promising option; nevertheless further studies are necessary to establish definitively its tolerability and feasibility in clinical practice.

HDR brachytherapy treatment is usually delivered in a series of dose fractions in order to optimize its effectiveness and minimize side effects. Early and late complication can occur after brachytherapy. The most common early complications are represented by damage of pharynx, glottis, and perforation of airway and esophagus. Late complications include radiation bronchitis, stenosis, hemoptysis, and fistula formation. They may occur days or weeks after the therapy and case series indicate that such adverse symptoms occur in up to 42% patients (73–75). Brachytherapy might be curative in selected patients. Several experience evaluated the use of brachytherapy. In a series of 226 patients with NSCLC not eligible for surgery or external beam radiation therapy HDR brachytherapy was used. At 3 months, 94% of patients had a complete endoscopic response. The 2 and 5 year OS and OFS were 57%, 29% and 81%, 56%, respectively (76). In another study 106 patients with endobronchial lung cancer were treated with HDR brachytherapy (6 sessions of 5 or 7 Gy over 5 weeks). An overall survival of 24% at 5 years was reported. Five deaths were attributed to the HDR-EBBT procedure (two from fatal hemoptysis and three from bronchial necrosis) (77). In summary, data on brachytherapy in the setting of LA NSCLC are few and heterogeneous. Thus its role is still not established and more studies are necessary.

Re-treatment Brachytherapy

Brachytherapy involve the placement of radioactive source within or in proximity of malignancy with the goal to provide local radiation treatment. Endobronchial brachytherapy requires implantation or insertion of a radioactive source into a patient’s airway. This approach is used in particular for palliation and is rarely considered as radical treatment. Two different brachytherapy techniques can be applied: “low-dose rate” (LDR) and “high-dose rate” (HDR). LDR implies delivery of less than 2 Gy/hor and a total dose of 15 to 50 Gy, given over up to three days. LDR brachytherapy requires manual manipulation of the radionuclide, 30 to 70 hours of treatment, and cumbersome radiation protection measures. HDR (Iridium-192) involves dose rate of 10 to 12 Gy/hour, with the total dose ranging from 5 to 40 Gy, and the dose per session (fraction) varying from approximately 3 to 10 Gy.

Patients affected by thoracic relapse of primary lung malignancies after a first course of definitive radiotherapy have limited therapeutic possibilities, and they are often treated with palliative intent only. Re-irradiation with modern and precise technique represents an appealing treatment strategy, due to the optimized dose distribution that allows for high-dose delivery with better sparing of organs at risk. This approach has the objective to maximize LC. Several results indicate that thoracic radiation retreatment could guarantee promising disease control in selected patients. In case of small volume thoracic relapse, using hypofracionation regimen, 1-year and 2-year LC rates ranged between 59% and 95% and between 50% and 92%; 1year and 2-year OS rates ranged between 59% and 80% and between 29% and 74%, respectively (78–79). However, the data on outcome and toxicity are derived from low-quality retrospective studies, and

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results should be cautiously interpreted. Re-irradiation could lead to serious side effects; when curative doses are prescribed, the major risk is radiation pneumonitis, occurring in around 20% of cases, and it is mainly related to an excess of dose to healthy lung (80). Thus, when re-irradiation is considered, accurate patients’ selection remains the crucial point to evaluate. In summary, given the paucity of evidences available at present, the indication for thoracic re-irradiation with curative intent should be based on a strictly individualized risk-benefit decision.

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Conclusion The association of chemotherapy and radiotherapy represents the gold standard in the treatment of LA NSCLC. Nevertheless, local control and overall survival is still considered unsatisfactory. Previous clinical studies established the role of high radiation dose with an increase of clinical outcomes. However, RTOG 0617 trial seems to exclude this assumption suggesting that dose escalation strategy is not able to increase LC and OS outcomes. Hypofractionated radiation treatment is commonly used in UK with an acceptable toxic profile, but no phase III studies are still data. Preliminary results with the use of proton therapy showed promising OS and limited toxicity to the lung and esophagus but longer follow-up is necessary. The use of stereotactic technique as a boost after conventional course of radiotherapy can be considered an intriguing approach but it is in infancy. Isotoxic radiotherapy prescriptions are a promising option but more studies are necessary to establish its tolerability and feasibility. To date, conventional fractionation and a dose prescription of 63–66 Gy is still considered the standard radiation choice. The use of new approaches, new technological tools (Image guided Radiotherapy, intensity modulated radiotherapy and use of adaptive radiation prescription) in association with standard chemotherapy and/or new target therapy still deserve to be explored in clinical trials in order to increase outcomes in NSCLC LA.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

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What is changing in radiotherapy for the treatment of locally advanced nonsmall cell lung cancer patients? A review.

Radiotherapy treatment continues to have a relevant impact in the treatment of nonsmall cell cancer (NSCLC). Use of concurrent chemotherapy and radiot...
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