Large volume unresectable locally advanced non-small cell lung cancer: acute toxicity and initial outcome results with rapid arc

Lung cancer remains the major cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) account for at least 80% of all lung tumors and about 30% of them present with unresectable locally advanced disease at diagnosis (stage IIIA-IIIB) [1]. Until the mid 1980s standard treatment of patients with inoperable locally advanced NSCLC consisted of radiotherapy (RT) alone with a median survival time of 10 months[1]. From data about lung cancer population diagnosed in the second half of 1990s, overall survival at one and two years was estimated of 36% and 12% respectively[2].

Rates at 2 and 5 years of 15% and 5% respectively [3]. In attempts to improve the survival in these patients, chemotherapy was added to external beam irradiation. Several trials have been positive in favour of combined therapy [4‐6]. More recently, other clinical trials have shown that, in selected patients (good performance status, age ≤ 75 years and minimal weight loss) concomitant platinum-based chemo-radiotherapy is feasible with improvement in progression-free survival and overall survival (OS) in comparison with sequential chemo-radiotherapy (OS 4 years 21% vs. 14%) [7]. However, survival for patients with unresectable locally advanced NSCLC is extremely poor with high rates of loco-regional failure. Recent trials suggest that dose escalation RT could improve loco-regional control with likely benefit on overall survival [8‐10]. Rengan et al reviewed the treatment of stage III tumors with large gross tumor volumes (GTV) using 3D-CRT, founding 10 Gy increase in dose to be correlated with a 36.4% decrease in local failure rates [9]. Unfortunately, the large volume of tumor makes dose escalation difficult when using 3D-CRT, since, to avoid treatment related complications such as severe pneumonitis, it is necessary to keep the mean lung dose (MLD) below 20Gy approximately [11].

More recently, the development of intensity modulated radiotherapy (IMRT) makes it possible to deliver a high therapeutic effective dose to the target volume with maximum preservation of surrounding normal tissues. Many studies have compared IMRT and 3D-CRT plans for patients with large unresectable locally advanced NSCLC. Results show statistically significant differences in V20, V30 and MLD for contralateral lung with the values in the IMRT plans being lower. The benefits seemed most pronounced in medium to large tumours [12].

A recent retrospective clinical trial of MSKCC reported a 2-year local control and overall survival of 58% and 58% respectively and a median survival time of 25 months for patients with inoperable stage III lung cancer and treated with 70 Gy (range 60-90 Gy) using IMRT [13]. The results of this study suggest that dose escalation could have an effect not only on local control but also on survival.

To implement dose escalation strategy on NSCLC, advanced IMRT delivery technologies such as Helical Tomotherapy were used and compared with three-dimensional conformal radiotherapy in the clinical practice[14, 15]. Both Helical Tomotherapy, and to a lesser extent conventional three-dimensional conformal radiotherapy, have shown the potential to significantly decrease radiation dose to lung and other normal structures in the treatment of NSCLC, providing important implications, in terms of acceptable acute toxicities recorded, for dose escalation strategies in the future[15, 16]. In a report of volumetric changes, measured in the primary tumor on megavoltage-computed tomography (MVCT) during chemoradiation, Helical Tomotherapy showed also to be effective in reduce tumour volume in NSCLC[17].

RapidArc(RA), a volumetric modulated arc therapy based on the original investigation of K. Otto [18], has been recently introduced in clinical practice in several institutes after an intensive validation at planning level, compared to IMRT or other approaches, in a series of studies including brain tumours, prostate, head and neck, mesothelioma, cervix uteri and other indications [19‐25].

RA is implemented as the Progressive Resolution Optimisation (PRO) algorithm in the Eclipse planning system by Varian Medical System (Palo Alto, California, USA). The optimisation process is based on an iterative inverse planning process that aims to simultaneously optimise the instantaneous multi-leaf collimator (MLC) positions, the dose rate, and the gantry rotation speed in order to achieve the desired dose distribution.

In this study, our aim was to investigate the potential of RA to deliver a therapeutic dose to large volume unresectable NSCLC. We also investigated the possibility of sparing lung tissue, esophagus, heart and spinal cord using RA with the aim of paving the way for further study of dose escalation In the present study, acute toxicities and initial outcome results, were evaluated and reported.

Twenty-four patients with large volume NSCLC were treated with a median dose of 66 Gy (range:50-66 Gy) or more using RA from May 2009 to September 2009. All patients had tumors that were unresectable for site and stage. Eleven patients were stage IIIB and 13 patients stage IIIA. Eleven selected patients (age < 70 years, minimum weight loss < 10% 6 months before diagnosis, and PS 0) were treated with concurrent platinum-based chemo-radiation therapy. Eight patients were treated with sequential chemo-radiotherapy, and 5 patients with RT alone because unfit for chemotherapy or elderly.

Only early results are available regarding clinical outcomes. As planned, there were no interruptions during the course of the radiation treatment. No patients had acute skin toxicity. Esophageal toxicity was mild. No Grade 3 toxicity occurred. Grade 1 and Grade 2 acute esophageal toxicity occurred in 22/24 and 2/24 patients respectively. Persistent cough requiring narcotic and antitussive agents occurred in 10/24 patients. For sub-acute toxicity, asymptomatic pneumonia occurred in 6 patients (four grade 1, and two grade 2) who underwent concurrent chemo-radiotherapy at 45 days from the end of treatment and regressed with antibiotic therapy, without hospitalization. Compared with exclusive radiotherapy group, hematologic toxicity was higher in Chemoradiation one, but there was not acute toxicity > Grade 3 or interruptions. There wasn't an important effect of side effects on weight loss for the population of study and PS was not significantly reduced during treatment. The median follow-up time was 6 months.

A partial remission > 50% was seen at three months in 56% (14/24) of patients, a partial remission < 50% in 22% (5/24) and stable disease in 22%. No progressive disease occurred. Figure 1 shows a case of significant remission (> 75%) at 5 months after completion of radiotherapy as detected with routing CT scan during follow-up.

Figure 2 shows examples of dose distributions for one patient. Colour wash is in the interval from 7 to 71Gy. GTV, PTV and organs at risk are outlined as solid lines in the images. Figure 3 reports the average dose volume histograms for GTV, PTV, organs at risk and healthy tissue. Lines represent the inter-patient variability at one standard deviation.

Table 4 summarizes the technical features of the treatment characteristics. Results of the DVH analysis are reported in Table 2 for PTV and GTV, and in table 3 for organs at risk and healthy tissue, together with the specific objectives.

Dosimetric data showed that RapidArc obtained the achievement with respect to planning objectives for most of the parameters considered. In particular, the target coverage and dose homogeneity are well achieved, even in regions with highly demanding heterogeneities (GTV well within the thresholds of 95% and 107%). In terms of organs at risk the contralateral lung presented promising results, while keeping the maximum significant dose to the spinal cord well below the tolerance level. Heart irradiation was not of major concern for the selected patients due to the relatively cranial target location. The oesophagus volume irradiated to doses higher than 55Gy is in average higher than objective by about 3%, but this value is largely dependent on the organ volume included inside the target volume. As expected from an intensity modulation arc technique the low dose bath is not negligible, showing about 8000 cm³ of tissue irradiated at 10Gy dose level.

Pre-treatment quality assurances of RA plans resulted in an average gamma agreement index GAI 3% superior to the acceptance threshold of 95% set as a reference in our institute.

Despite an improvement in survival the prognosis of patients with unresectable local advanced NSCLC (stage IIIA-IIIB) remains poor both for locoregional failure and for distant metastatic disease. Concurrent chemo-radiation is at present the standard of care. Given that local recurrence is the leading cause of death in this patient population, techniques for improving local control may have a positive impact on survival rates and quality of life. The value of dose escalation was demonstrated in a study from MSKCC; Rengan et al founded that a 10 Gy increased in dose correlated to a 36.4% decrease in local failure rates [9]. Unfortunately, the extension of disease and the presence of surrounding HT makes it often difficult to deliver high doses with curative intent.

Based on the results of an intensive program of pre-clinical investigations performed at planning level [19‐25] for assessing the reliability and potential benefit of RA, this technique has been used in clinical practice for a variety of indications at our Institute since November 2008. The present study reports the early findings from the treatment of a group of 24 patients affected by advanced lung cancer irradiated with RapidArc.

The main objective in the initial clinical introduction of RA is the evaluation of the possibility to provide RT treatments respecting a set of planning objectives. These results should be achieved without introducing elements of potential confusion like alterations of the fractionation schemes (acceleration or hypo-fractionation for example) or dose escalation [14]. Further studies will assess the elements of improvement once the safety of the new approach is consolidated in routine practice. These results could enable the activation of a second phase dose trial aiming to push RapidArc towards improved sparing of organs at risk, particularly the contra-lateral lung.

Having achieved the result of respecting or improving most of the planning objectives, RapidArc confirmed also some advantages at a logistical level. It provided a significant efficiency in dose delivery treatment time,. This is a particularly important point for patients presenting advanced lung cancer, who might have breathing difficulties in supine position, or even coughing if lying for a long time: shortening the time spent on the couch permits the treatment for this class of patients.

From the clinical point of view, the data presented here are encouraging, confirming that RA can be considered as a safe modality for this category of patients having proved limited impact in terms of acute toxicity [32, 33]. The smoother process of RA and its potential reduction in acute toxicity could also lead to a more uniform duration of treatments, reducing the risk of unscheduled and undue interruptions.

In particular, the authors point out the extension of disease to be greater than other population finding in literature. Sura et al. [13] report mean PTV volume of 459 cm³, much smaller than our series, where mean PTV volume was 818 cm³, thus corroborating our results.

It is obvious that the present study cannot be considered as conclusive and that long-term observation of patients is needed to define outcome and late toxicity. These preliminary results are encouraging additional experience in this field. Further investigations will aim to look at the long term clinical outcome and late toxicity as well as improvements in sparing of the organs at risk.

Twenty-four patients with large volume unresectable locally advanced lung cancer were treated with RA at Istituto Clinico Humanitas. Quality of treatments resulted in a general fulfilment of the planning objectives. Clinical outcome for early acute toxicity showed limited events. Future investigations will aim to increase sparing of organs at risk and to look to long-term outcome based on the fact that the first phase has achieved the primary goal of demonstrating the safety and efficacy of RA.