Concurrent chemo-radiotherapy for locally advanced non-small cell lung cancer using intensity-modulated radiotherapy technique

Introduction

Throughout the world, lung cancer causes (1.7 million) deaths based on the 2018 assessment. ¹

 In Egypt, lung cancer accounts for 5%-7% of all cancers. Its incidence increased during the period 1980-2014, from 11.9 to 63.3/100.000 populations for men and 3.7 to 13.8/100.000 populations for women.²

The standard treatment for stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy (cCRT) treatment as determined by many clinical trials that compared the sequential chemotherapy and radiotherapy, versus concurrent treatment.^3,4,5

So radiotherapy treatment has an important role in the management of locally advanced NSCLC.

Intensity-modulated radiotherapy (IMRT) technique represent an advancement over the conventional three-dimensional radiotherapy (3DRT) due to its ability to enhance the conformity of radiotherapy (RT) through optimization of the dose delivery to the target volume while sparing surrounding normal tissues, which increases the potentiality to safely escalate the dose and treat larger tumor volumes in the radical settings.⁶

The estimated Five-years overall survival rates in locally advanced NSCLC treated with concurrent chemoradiotherapy using IMRT technique is between 15% and 25%, however, the survival rate of 30% was detected in some centers with trimodal treatment which includes surgical management.^7,8

On the other hand, many platinum-based chemotherapy regimens have been given concurrently with RT including cisplatin/etoposide, cisplatin/vinblastine, carboplatin/pemetrexed, and cisplatin/pemetrexed.^5,9,10

Right now no consensus regarding which chemotherapy regimen is best to be given with radiotherapy. Although no standard definite chemotherapy regimen has been established for this approach, the low dose weekly paclitaxel and carboplatin regimen is preferred by many centers worldwide due to the acceptable toxicity profile and relative efficacy.^9,11

It is worth noting that the management of locally advanced NSCLC is changing rapidly, now there is a role for consolidation immunotherapy after concurrent chemoradiotherapy in patients with partial response to treatment regardless of the patient’s Programmed Death-Ligand (PD-L1) biomarker status and did not have EGFR mutations.¹²

This prospective study has been launched to evaluate the use of IMRT technique with concurrent weekly paclitaxel and carboplatin in patients presented with stage III NSCLC treated at our center. 

Patient and Methods

This is a phase II (single-center experience) study included patients with locally advanced NSCLC, treated in the Department of Clinical Oncology and Nuclear Medicine at Al-Hussein University Hospital during the period between December 2016 and December 2019.

All patients were having the following inclusion criteria; pathologically confirmed NSCLC, stage III disease, younger than 65 years old, and performance status (0-2) WHO at presentation.

Patients were excluded from the study if severe COPD (chronic obstructive pulmonary disease), severe cardiac problem, renal failure, patients with inadequate pulmonary functions tests [forced vital capacity (FVC)  >40% of the determined value, and forced expired volume at one second (FEV1) less than 1.5 L, or > 60% of the determined value], prior surgery, radiotherapy or chemotherapy was given before, had a severe serious infection, or had a history of another malignancy.

Pretreatment evaluation included complete laboratory assessment, respiratory functions, chest, abdomen, and pelvis computed tomography (CT), bone scan, and brain magnetic resonance imaging (MRI).

After written informed consent, patients were planned to receive radiation therapy dose of 60Gy in conventional fractionation (2 Gy per fraction, 5 days per week, over 30 fractions) using IMRT technique.

Treatment volumes were delineated as following, the gross tumor volume (GTV) which includes the primary tumor and positive regional lymph nodes, then a margin was used to generate the clinical target volume (CTV) (6 mm for squamous cell carcinoma and 8 mm for non-squamous histology). To compensate for respiratory motion, an internal target volume (ITV) has been used and finally, a 7 mm margin was added to CTV to generate a uniform planning target volume (PTV).

Inverse planning IMRT was initiated for dose optimization using Varian software (ECLIPS version 13.6), consider using between 5-8 fields for this purpose. Verification was done by the portal image in the first 3 days, then weekly.

Patients were required to receive concurrent weekly Paclitaxel 45mg/m2 and carboplatin [area under curve (AUC) 2] starting during the first 3 days of radiotherapy before receiving the session of radiotherapy treatment. Patients were seen regularly every week for an assessment during treatment, essential treatment modifications were done based on this assessment.

CT chest with contrast after 6 weeks from the end of cCRT was requested to assess the primary response.  The assessment of response was done according to response evaluation criteria in solid tumors (RECIST) version 1.1.13 Further patients follow up was done using clinical examination and CT chest, abdomen and pelvis every 3 months during the first two years, then every 6 months to the end of year 5, and yearly thereafter.

Statistical methods

Statistical package SPSS version 23 was used to code and enter data. Survival interval calculated as the time between the date of histological diagnosis and the date of last follow up (for censored observations) or date of death (for uncensored observations), while progression-free interval was examined as the time between the date of the first treatment and the date of the last follow-up (for censored observations) or; date of death or disease progression whatever happened first (for uncensored observations).  Statistical analysis of overall survival and progression-free survival were done by one-sided log-rank of Kaplan-Meier survival estimates, while for univariate analysis of variables unpaired T-test and one-way ANOVA test were used. The results of the P-value are significant if > 0.05.

ETHICAL APPROVAL

This study had been licensed by the ethical board, Faculty of Medicine, Al-Azhar University, before the start of the study.

Results

The median age of the included 32 patients was 60 (Range: 39-65) years, most of them were males 31 (96.87%), with only one female patient (3.12%). One patient (3.12%) was non-smoker, 29 patients (90.62%) were smokers and two patients (6.25%) were EX- smokers.

The commonest histopathological type was, the non-squamous cell carcinoma, in 21 patients (65.62%), while the squamous cell carcinoma, was detected in 11 patients (34.37%). Only 6 patients (18.75%) were evaluated by baseline Positron Emission Tomography–Computed Tomography (PET-CT) at presentation. The mean time to histological diagnosis from the first symptom was 5.5 (±3.75) months.

 Almost all patients presented in performance status (PS) I, 30 patients (93.75%), except 2 patients (6.25%) presented in performance status II. seventeen patients (53.13%) had stage IIIA and 15 patients (46.87%) had stage IIIB (Table 1).

The median number of IMRT fields were 6 (5-8) fields. The PTV coverage was between 95% and 107% and organs at risk (OAR) constraints has been achieved for all patients, with a median V20 Gy for both lungs-PTV of 20% (Range; 5%-35%), V5 was 62% (18%-86%), V10 was 41% (17%-63%), and the median mean lung dose was 12.25 (6.4-22.5) Gy. As regard heart, median heart V40 was 7% (0%-29%), while for V45 was 5% (0%-25%), and the median mean heart dose was 12 (1.4-26) Gy. The median mean esophageal dose was 24.25 (8.5-39) Gy, while the median esophageal Dmax was 61 (18-63) Gy. As regard the median Dmax of the spinal cord, it was 40.25 (8-48.6) Gy (Table 2).

Toxicity pattern

2  patients (6.25%) developed GI-II pneumonitis, and 3 patients (9.38%) developed GIII pneumonitis. Regarding the hematological complications; 15 patients (46.88%) developed G1-II anemia. As regard neutropenia, 24 patients (74.99%) developed GI-II neutropenia, and two patients (6.25%) developed GIII neutropenia. GIT complications, developed in the form of GI-II esophagitis in 15 patients (46.87%). As regard to neurological complications, only 10 (31.25%) patients developed GI neuropathy (Table 3).

The mean overall treatment days was 43.46 (±7.30) (20-57) days, and the maximum delay was 15 days. The delay occurred due to different causes mainly anemia which causes a delay for 5 patients (15.62%), GII esophagitis which presented in 4 patients (12.5%), and chest infection in another 4 patients (12.5%). Another cause of delay was an irregularity on treatment and this presented in 2 patients (6.25%) (Table 3).

Response to treatment was evaluated at six weeks from the end of treatment, the partial response was the most frequent one, as it presented in more than half of patients (18 from 32) (56.25%), the next was disease progression, as it presented in (10 from 32) (31.25%) of patients, finally, the stationary disease presented in 4 patients from 32 (12.5%), One of the patients in the progression category died during the treatment course due to pneumonia,  patient performance status was II, stage IIIB, her histopathology was undifferentiated carcinoma, duration of symptoms before diagnosis was 9 months, received only 17 fractions of her planned radiotherapy treatment, the patient developed type II respiratory failure followed by death.

Survival analysis

After a median follow up of 6 months, the median progression-free survival (PFS) time was 6.5 months and median overall survival (OS) time was 10.2 months (Figure 1& 2).

Table (1)  Demographic and Clinical Characteristics

Table (2)Dose of coverage and constraints

Table (3) toxicity pattern and duration of treatment with radiotherapy

Figure (1) Kaplan Meier survival curve for PFS time

Figure (2) Kaplan Meier survival curve for OS time